Developing Oral LT3 Therapy For Heart Failure With Reduced Ejection Fraction
Phase: PHASE1
Conditions: Heart Failure With Reduced Ejection Fraction (HFrEF), Low T3 Syndrome
Sponsor: University of Pennsylvania

 
05/11/2022 
 
 
 
DEVELOPING ORAL LT3 THERAPY FOR HEART FAILURE (DOT3HF) 
 
 
Principal Investigator (1) 
Anne R. Cappola, M.D., Sc.M. 
DOM: Division of Endocrinology 
Smilow TRC 12, Room 136 
215-573-5359 
acappola@pennmedicine.upenn.edu 
 
Co–Principal Investigator (2) 
 
 
Thomas P. Cappola, M.D., Sc.M. 
DOM: Division of Cardiovascular Medicine 
11 South Pavilion, Room 11-113  
(215) 662-3140  
thomas.cappola@pennmedicine.upenn.edu 
 
 
Co–Principal Investigator (3) 
 
 
 
 
 
 
 
Sponsor 
 
 
Julio A. Chirinos, M.D., Ph.D., FAHA, FESC 
DOM: Division of Cardiovascular Medicine 
11 South Pavilion, Room 11-138.  
215-573-6606  
julio.chirinos@pennmedicine.upenn.edu 
National Institutes of Health   
National Heart, Lung and Blood Institute 
NIH Grant Number                    
 
HL146390  
 
Investigational Product: 
 
Liothyronine (LT3) 5 mcg tablet formulation (IND Exempt)  
 
IRB Number: 
 
833681   
 
ClinicalTrials.gov Number       
 
NCT04111536 / NCT04112316 
 
 
Initial version 
 7/09/19 
Amended 
9/23/2019 
Amended 
01/30/2020 
Amended  
10/21/2021 
Amended  
5/11/2022 
 

  
05/11/2022 
 
 
 
Table of Contents 
 
Contents 
LIST OF ABBREVIATIONS ...................................................................................................... IV 
STUDY SUMMARY ................................................................................................................... 1 
1 
BACKGROUND AND STUDY RATIONALE ...................................................................... 4 
1.1 
BACKGROUND AND RELEVANT LITERATURE ................................................................... 4 
1.2 
INTERVENTIONAL AGENT:  LIOTHYRONINE (L-TRIIODOTHYRONINE OR LT3) ....................... 6 
1.2.1 Nonclinical Data ...................................................................................................... 6 
1.2.2 Clinical Data to Date ............................................................................................... 6 
1.3 
DOSE RATIONALE (IF APPLICABLE) ................................................................................. 7 
2 
STUDY OBJECTIVES ....................................................................................................... 8 
2.1 
PRIMARY OBJECTIVE .................................................................................................... 9 
2.2 
SECONDARY OBJECTIVES ............................................................................................. 9 
3 
INVESTIGATIONAL PLAN ................................................................................................ 9 
3.1 
GENERAL DESIGN ........................................................................................................ 9 
3.1.1 Screening Phase ...................................................................................................10 
3.1.2 Study Intervention Phase .......................................................................................10 
3.1.3 Follow Up Phase ....................................................................................................11 
3.1.4 Allocation to Interventional Group ..........................................................................11 
3.1.5 Primary Study Endpoints .......................................................................................11 
3.1.6 Secondary Study Endpoints ...................................................................................11 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION .......................................12 
4.1 
MAJOR INCLUSION CRITERIA ........................................................................................12 
4.2 
EXCLUSION CRITERIA ..................................................................................................12 
4.3 
PARTICIPANT RECRUITMENT ........................................................................................13 
4.4 
DURATION OF STUDY PARTICIPATION ...........................................................................14 
4.5 
TOTAL NUMBER OF PARTICIPANTS AND SITES ...............................................................14 
4.6 
VULNERABLE POPULATIONS .........................................................................................14 
5 
STUDY INTERVENTION ...................................................................................................14 
5.1 
DESCRIPTION ..............................................................................................................14 
5.2 
STUDY INTERVENTION REGIMEN ...................................................................................15 
5.3 
RECEIPT .....................................................................................................................15 
5.4 
STORAGE....................................................................................................................15 
5.5 
PREPARATION AND PACKAGING ....................................................................................15 
5.6 
BLINDING ....................................................................................................................15 
5.7 
ADMINISTRATION AND ACCOUNTABILITY ........................................................................16 
5.8 
PARTICIPANT COMPLIANCE MONITORING ......................................................................16 
5.8.1 Return or Destruction of Investigational Product ....................................................16 
6 
DETAILED STUDY PROCEDURES .................................................................................17 

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6.1 
SCHEDULE OF ASSESSMENTS ......................................................................................19 
6.2 
STUDY INTERVENTION VISITS .......................................................................................19 
6.3 
PARTICIPANT WITHDRAWAL .........................................................................................21 
6.3.1 Data Collection and Follow-up for Withdrawn Participants .....................................21 
6.4 
EARLY TERMINATION VISITS .........................................................................................21 
7 
STATISTICAL PLAN ........................................................................................................22 
7.1 
PRIMARY ENDPOINT ....................................................................................................24 
7.2 
SECONDARY ENDPOINTS .............................................................................................24 
7.3 
STATISTICAL METHODS ................................................................................................24 
7.3.1 Interim Analysis .....................................................................................................26 
7.4 
PARTICIPANT POPULATION(S) FOR ANALYSIS ................................................................26 
8 
SAFETY AND ADVERSE EVENTS ..................................................................................26 
8.1 
DEFINITIONS ...............................................................................................................26 
8.1.1 Adverse Event .......................................................................................................26 
8.1.2 Suspected Adverse Reaction .................................................................................26 
8.1.3 Serious Adverse Event ..........................................................................................26 
8.1.4 Unanticipated Problems(UP) Involving Risk to Participants or Others ....................27 
8.1.5 Preexisting Condition .............................................................................................27 
8.1.6 General Physical Examination Findings .................................................................27 
8.1.7 Post-study Adverse Event ......................................................................................27 
8.1.8 Hospitalization, Prolonged Hospitalization or Surgery ............................................28 
8.2 
RECORDING OF ADVERSE EVENTS ...............................................................................28 
8.3 
CLASSIFICATION OF ADVERSE EVENTS .........................................................................28 
SEVERITY ...............................................................................................................................28 
RELATEDNESS ........................................................................................................................29 
Expectedness ....................................................................................................................29 
8.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ...............................30 
8.4.1 Adverse Event Reporting Period ............................................................................30 
8.4.2 Expedited Reporting of Adverse Events and Unanticipated Problems ...................30 
8.4.3 Follow-up report .....................................................................................................31 
8.5 
MANAGEMENT OF ADVERSE EVENTS-CRITERIA FOR STUDY DRUG DISCONTINUATION .....32 
8.6 
UNBLINDING PROCEDURES ..........................................................................................32 
8.7 
STOPPING RULES ........................................................................................................32 
8.8 
OVERSIGHT AND MONITORING ......................................................................................32 
8.8.1 Data and Safety Monitoring Plan ...........................................................................32 
8.8.2 DATA SAFETY MONITORING BOARD ..............................................................................32 
. .............................................................................................................................................33 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .....................33 
9.1 
CONFIDENTIALITY ........................................................................................................33 
9.2 
DATA COLLECTION AND MANAGEMENT .........................................................................33 
9.3 
RECORDS RETENTION .................................................................................................34 
10 STUDY MONITORING, AUDITING, AND INSPECTING ...................................................34 
10.1 
STUDY MONITORING PLAN ...........................................................................................34 
10.2 
AUDITING AND INSPECTING ..........................................................................................34 
11 ETHICAL CONSIDERATIONS ..........................................................................................34 
11.1 
RISKS .........................................................................................................................35 
11.2 
BENEFITS....................................................................................................................36 
11.3 
RISK BENEFIT ASSESSMENT.........................................................................................36 

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11.4 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ..............................................36 
12 STUDY FINANCES ...........................................................................................................36 
12.1 
FUNDING SOURCE .......................................................................................................36 
12.2 
CONFLICT OF INTEREST ...............................................................................................36 
12.3 
PARTICIPANT STIPENDS OR PAYMENTS .........................................................................36 
13 PUBLICATION PLAN .......................................................................................................37 
14 REFERENCES ..................................................................................................................37 
15 ATTACHMENTS ...............................................................................................................41 
16 APPENDIX ........................................................................................................................41 
16.1 
SOURCE DOCUMENTS .................................................................................................42 
16.2 
CASE REPORT FORMS (CRFS).....................................................................................42 
 
 
 

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List of Abbreviations 
 
 
 
 
 
 
 
 
 
 
 
AE            
adverse event 
BNP 
B-type natriuretic peptide 
CHPS 
Center for Human Phenomic Science 
CVD 
cardiovascular disease 
CRT 
cardiac resynchronization therapy 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FT4 
free thyroxine 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
HFpEF 
heart failure with preserved ejection fraction 
HUP 
Hospital of the University of Pennsylvania 
ICD 
implantable cardioverter-defibrillator 
IDS 
Investigational Drug Services Pharmacy 
IRB 
Institutional Review Board 
IV 
intravenous 
KCCQ 
Kansas City Quality of Life Questionnaire 
LT3 
liothyronine 
LV 
left ventricular 
NIH 
National Institutes of Health 
NHLBI 
National Heart Lung and Blood Institute 
NT-pro-BNP 
N-terminal pro hormone B-type natriuretic peptide 
PHI 
protected health information 
REE 
resting energy expenditure 
SD 
standard deviation 
ThyPRO 
Thyroid-specific Patient Reported Outcome Measure 
T3 
triiodothyronine 
T4 
thyroxine 
TSH 
thyroid stimulating hormone 

Developing Oral LT3 Therapy for Heart Failure 
 
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05/11/2022 
 
 
Study Summary 
Title 
DEVELOPING ORAL LT3 THERAPY FOR HEART FAILURE 
(DOT3HF) 
Short Title 
Developing Oral LT3 Therapy for Heart Failure  
IRB Number               
 
833681   
Phase 
Phase I/II 
Methodology 
 
 
Parallel, Randomized, Double-Blind, Placebo-Controlled Crossover 
Clinical Trial  
 
Study Duration 
 
48 Months 
Study Center(s) 
Single-Center: University of Pennsylvania Health System 
Objectives 
 
The primary objective is to evaluate the safety of oral LT3 in heart failure 
with reduced ejection fraction (HFrEF) and heart failure with preserved 
ejection fraction (HFpEF) 
 
The secondary objective is to evaluate the feasibility and preliminary 
efficacy outcomes of oral LT3 therapy in HFrEF and HFpEF. 
 
Number of 
Participants 
28 in HFrEF arm and 28 in HFpEF arm, totaling 56 randomized 
participants 
Main Inclusion and 
Exclusion Criteria 
Inclusion: ≥18 years; NYHA Class I,II or III heart failure; normal TSH 
and free T4 levels; Total T3 level <94 ng/dL 

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 
HFrEF inclusion -  Left ventricular (LV) ejection fraction (EF)≤40 
percent, an implantable cardioverter-defibrillator (ICD), on stable 
doses of neurohormonal blockade for 30 days 
HFpEF inclusion - dyspnea on exertion and/or clinical evidence of 
heart failure by history and physical examination, LV EF40 percent,  If 
taking antihypertensive medications, beta-blockers, SGLT2 inhibitors, 
sacubitril/valsartan, or aldosterone antagonists, doses must be stable 
for at least 30 days and elevated filling pressures as evidenced by at 
least 1 of the following:  
1. Mitral E/e’ ratio > 14 (either lateral or septal) 
2. Mitral E/e’ ratio > 8 (either lateral or septal), with low e’ velocity 
(septal e’<7 cm/sec or lateral e’< 10 cm/sec), in addition to one 
of the following: 
a. Enlarged left atrium (LA volume index >34 ml/m2)  
b. Chronic loop diuretic use for control of symptoms 
c. Elevated natriuretic peptides (BNP levels >100 ng/L or 
NT-proBNP levels >300 ng/L) 
d. Tricuspid regurgitation velocity >2.8 m/s 
3. Elevated invasively-determined filling pressures previously 
(resting LVEDP >16 mmHg or mean pulmonary capillary 
wedge pressure [PCWP] >12 mmHg; or PCWP/LVEDP ≥25 
mmHg with exercise) 
4. Acute heart failure decompensation with radiographic evidence 
of pulmonary venous congestion or alveolar edema, requiring 
IV diuretics within the past year 
5. Probability of HFpEF>90% according to the HFpEF score, 
without a more likely clinically apparent cause for symptoms, 
as per investigator assessment 
Exclusion: Hypertrophic or restrictive cardiomyopathy; uncorrected 
severe primary valvular disease;; inability to perform VO2max exercise 
testing; severe lung disease; serum creatinine > 3.0 mg/dL; history of 
cirrhosis; acute coronary syndrome or coronary artery intervention or 
ablation therapy within past 2 months; cardiac surgery, percutaneous 
repair of a valve or septal defect, or initiation of cardiac 
resynchronization therapy within the past 6 months; chronic intravenous 
inotrope therapy; ventricular assist device therapy; heart failure 
hospitalization within past month; taking thyroid extract, LT4, LT3, 
amiodarone, or medication that affects the absorption or metabolism of 
thyroid hormone; gastrointestinal conditions that affect the absorption of 
thyroid hormone; current or planned pregnancy within the timeframe of  
study participation. 
 
Investigational         
Product (drug, 
biologic, device, 
etc.) 
For Drug, food, 
cosmetic, etc. 
include the dose, 
 
 
 
Oral Liothyronine, 5 mcg tablet, dose range from 2.5 mcg three times 
a day to 12.5 mcg three times a day 
 
 

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route of 
administration and 
dose regimen 
 
 
 
 
 
 
 
Duration of 
administration (if 
applicable) 
Eight Weeks  
 
Reference therapy 
Placebo 
Statistical 
Methodology 
Safety data will be monitored and reported by descriptive statistics 
where applicable. Rhythm monitoring will be described using 
measures of central tendency and variation, as well as frequencies 
and percentages. Frequencies and percentages will be used to 
describe participants with T3 levels above the upper limit of reference 
range (180 ng/dL) at the completion of each drug. 
Safety Evaluations  
 
Safety evaluations will be the frequency of safety events while on 
placebo compared to while on LT3, T3 levels, and rhythm monitoring. 
Data and Safety 
Monitoring Plan  
 
 
All safety events will be assessed in real time and at study completion 
by the PI’s. This study will also have a DSMB in place to review 
participant safety data and study conduct and progress (biannually or 
at DSMB determined frequency). In addition, an internal study monitor 
will provide study oversight biannually. 
 

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Introduction 
 
This study will be conducted in full accordance all applicable University of Pennsylvania Research 
Policies and Procedures and all applicable Federal and state laws and regulations including [as 
applicable include the following regulations as they apply 45 CFR 46, 21 CFR Parts 50, 54, 56, 
312, 314 and 812 and Good Clinical Practice]. 
 
1 
Background and Study Rationale 
1.1 
Background and Relevant Literature  
 
Heart failure is the most common reason for adult hospitalization in the developed world.1,2 Many 
patients with heart failure have low levels of the thyroid hormone triiodothyronine (T3). Therapies 
that target reversible causes of myocardial and peripheral organ dysfunction are likely to provide 
added benefit in heart failure with reduced ejection fraction (HFrEF). In addition, there are no 
proven effective pharmacologic therapies for heart failure with preserved ejection fraction 
(HFpEF), which accounts for ≥50% of the heart failure burden.3  
 
Triiodothyronine (T3), an endogenous thyroid hormone, exerts multiple effects on the 
cardiovascular system, mediated through T3 receptors in the myocardium and vasculature and 
directly on ion channels and mitochondria.4 Overarching effects of T3 include an increase in 
myocardial contractility and a decrease in systemic vascular resistance. Despite the high 
prevalence (~20-30%) of low T3 syndrome in heart failure,5,6 the exogenous administration of 
liothyronine (LT3), the synthetic form of T3, remains an underexplored therapeutic option. 
Approximately 20% of circulating T3 is produced directly from the thyroid, whereas the remaining 
80% is produced from the conversion of circulating thyroxine (T4) to T3. 
 
Low T3 syndrome has been associated with increased mortality in patients with HFrEF6-8 and 
disease severity in HFpEF9, but whether it is a marker of poor health or a mediator of clinically 
relevant abnormalities in heart failure is unknown. The overall goal of this study is to determine 
the safety, feasibility, and preliminary efficacy of oral LT3 therapy in patients with Heart Failure 
(HF) and low T3.  
 
Proof of concept clinical studies using short-term intravenous LT3 infusions have demonstrated 
beneficial effects on biomarkers and safety in patients with ischemic HFrEF. However, knowledge 
gaps remain regarding the safety of oral LT3 therapy in HFrEF. Furthermore, no studies have 
examined LT3 safety in HFpEF.  
 
Low T3 is highly prevalent and predicts poor prognosis in patients with heart failure.  
Thyroid dysfunction is implicated as a poor prognostic factor in heart disease. The low T3 
syndrome, defined as a low T3 level with levels of TSH and free T4 within the normal reference 
range, is present in 20-30% of patients with HFrEF.5,6 The hypothesized mechanism of low T3 is 
through increased cytokine levels and hypoxia, which lead to decreased conversion of T4 to T3 
and increased clearance of T4 to reverse T3.4 Low serum T3 levels are associated with 
myocardial fibrosis and abnormalities in myocardial perfusion and metabolism in patients with 
idiopathic dilated cardiomyopathy.7 In studies of hospitalized patients with heart failure, low T3 
syndrome was independently associated with higher all-cause mortality.6,8,9 These data have 
recently been extended to outpatients with chronic heart failure.10  
 
Although less is known about the effects of low T3 in HFpEF, data from one cross-sectional study 

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of 89 patients with HFpEF found that 22% had low T3 syndrome.11 In addition, T3 levels below 
the median were associated with higher levels of BNP and greater severity of diastolic 
dysfunction. Our unpublished data show a 29% prevalence of low T3 syndrome in patients with 
HFpEF and associations of low T3 with worse cardiac function.  
 
LT3 has been available for over 60 years but has not been studied for this indication. 
Establishment of benefit/dosing and acceptable safety of LT3 therapy in patients with HFrEF 
and/or HFpEF is needed. In addition, feasibility and preliminary efficacy data produced could be 
used to design trials to test whether LT3 therapy, when dosed appropriately, can benefit patients 
with HF, definitively answering the question of whether or not to pursue larger studies of LT3 
administration in HF. 
 
HFrEF treatment rationale 
There are opportunities for improvement in treatment of HFrEF.  Current approaches to treatment 
of chronic HFrEF include device therapies that support myocardial function and 
pharmacotherapies that counteract the neurohormonal response to the failing heart. ICDs also 
improve outcomes by aborting sudden death from ventricular arrhythmia. Improved survival has 
been shown with cardiac resynchronization therapy (CRT), which has a direct effect on the 
myocardium, and with beta blockers, angiotensin-converting-enzyme inhibitors, angiotensin 
receptor-neprilysin inhibitors, hydralazine plus nitrate, and aldosterone antagonists, which curb 
the neurohormonal response. Certain therapies appear to have greater benefit in specific 
subpopulations of patients with HFrEF, such as hydralazine plus nitrates in blacks12 or ivabradine 
in patients with resting heart rate ≥70 beats per minute.13  
 
Despite the therapeutic success of CRT, previously developed drugs targeting ventricular function 
have had mixed experience. Potent oral and intravenous inotropes, which augment β1-adrenergic 
signaling through cAMP, acutely improve hemodynamics and symptoms in advanced disease, 
but have failed to show survival benefit and may be harmful with chronic administration, though 
such data were collected largely in the pre-ICD era.14-16 In contrast, milder inotropic agents, such 
as digoxin, lower the risk of heart failure readmission and may favorably affect survival in patients 
with therapeutic digoxin levels.17,18 An important lesson is that a precise understanding of the 
pharmacologic effects and dose-response in the cardiovascular system are essential steps in 
assessing therapeutic potential. Thyroid hormone is a key endogenous regulator of cardiac 
function and its effects require precise regulation: cardiac effects occur from thyroid hormone 
excess as well as deficiency. T3 deficiency is highly prevalent in HFrEF, but the therapeutic 
potential of correcting T3 levels in HFrEF has not been explored. 
 
HFpEF treatment rationale 
There is an urgent need to identify effective agents for the treatment of chronic HFpEF.  
Approximately half of HF is secondary to HFpEF, which is anticipated to represent an even larger 
proportion of the total burden of HF as the population ages.19 In contrast to chronic HFrEF, there 
is a pronounced paucity of effective interventions in chronic HFpEF, and no proven effective 
pharmacologic intervention to improve outcomes in this condition. Multiple phase 3 trials over the 
last few decades have failed to demonstrate a clear benefit of various pharmacologic 
interventions. Recent therapeutic successes have occurred in HFpEF, due to the appreciation of 
the importance of well-conducted early phase trials that characterize the mechanisms and dose-
response of specific interventions.20-28 Detailed hemodynamic and cardiac phenotyping has 
provided important insights into the pathophysiology of LV remodeling and fibrosis, diastolic 
dysfunction, microvascular disease, and impaired oxygen delivery to peripheral skeletal muscle, 
all of which contribute to exercise intolerance, the cardinal feature of HFpEF.3 Furthermore, 
heterogeneity in the underlying processes that contribute to HFpEF is increasingly recognized. 

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The ability to identify individuals with a specific abnormality (low T3) that can be targeted by a 
pharmacologic intervention represents a promising approach.29  
  
1.2 
Interventional Agent:  Liothyronine (L-triiodothyronine or LT3) 
Liothyronine (L-triiodothyronine or LT3) is the synthetic form of the natural thyroid hormone 
triiodothyronine (T3), available as the sodium salt.  LT3 is most often used to treat hypothyroidism 
and has been used for over 60 years.  Liothyronine is the active form of thyroxine, which is 
composed chemically of tyrosine with bound iodine. The half-life of LT3 is one to two days.30  
 
1.2.1 Nonclinical Data 
Preclinical studies support beneficial effects of T3 on myocardial contractility, myocardial 
relaxation, and vascular resistance. Molecular studies have elucidated the effects of T3 in 
cardiac myocytes. T3 enters the cardiomyocyte through membrane transporters, or it is produced 
intracellularly from conversion of T4 to T3 by type 2 deiodinase. T3 binds to nuclear receptors 
bound to thyroid hormone response elements present in the regulatory regions of target genes, 
acting to regulate the expression of a number of genes that encode key proteins including α and 
β myosin heavy chain, Na+K+ ATPase, sarcoplasmic reticulum Ca2+ ATPase, and 
phospholamban.4 Nongenomic effects of T3 are mediated through alterations in ion flux through 
ion channels such as the sarcolemmal Na+ channel, inward-rectifying K+ channel, and voltage-
activated potassium channels.31 Together, these cellular actions contribute to the inotropic and 
lusitropic effects of T3.  
 
Since intracardiac deiodination of T4 to T3 occurs, it would seem that as long as there were 
sufficient circulating T4, intracardiac T3 would be preserved. However, two studies in 
thyroidectomized rats have shown that LT4 administration fails to restore intracardiac T3 
levels.32,33 In addition, in a rat model of HF due to ischemic cardiomyopathy, infusion of LT3 
restored contractility to that of control animals.34 This has led to the hypothesis that the failing 
heart is a hypothyroid heart due to intracellular T3 deficiency, irrespective of circulating T4 
levels.35 
1.2.2 Clinical Data to Date 
1.2.2.1 Clinical Studies in Adults  
Research in humans suggests safety of oral LT3 in patients without pre-existing cardiac 
disease. 
In 1891, the use of thyroid extract, which was generated from ground sheep thyroid glands, was 
reported as the first successful treatment for hypothyroidism.36 Subsequent research led to the 
isolation of T4 in 1914 as the major hormone produced by the thyroid gland, and to commercial 
synthesis of LT4 in 1927 as an alternative to thyroid extracts.37 Since thyroid hormone medications 
were not new drugs, thyroid extracts and LT4 were exempt from the 1938 Food, Drug, and 
Cosmetic Act, which required that new drugs be tested for safety. They were permitted to remain 
on the market without testing. T3 was isolated from the thyroid gland and synthesized in 1954. 
Cytomel was the first LT3 medication to be approved in 1956. Thyroid medications were again 
grandfathered in after the 1962 overhaul of the Food, Drug, and Cosmetic Act, and their 
manufacturers never had to submit scientific data or get full FDA approval. Concerns among 
endocrinologists about adverse cardiac effects from high doses of LT3,38 recognition that T4 is 
converted to T3 peripherally,39 the longer half-life of LT4 compared to LT3, and aggressive 
marketing by the manufacturer of Synthroid led to dominance of LT4 thyroid hormone 

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replacement in the 1970’s.  
 
LT4 therapy remains the mainstay of treatment of hypothyroidism. LT3 is often added to a loading 
dose of LT4 in patients hospitalized with myxedema coma (5-20 mcg loading dose, followed by 
2.5-10 mcg every 8 hours).40 Despite its potential, use of LT3 therapy in other settings, such as 
in combination with LT4 therapy to treat hypothyroidism, is not currently recommended by the 
American Thyroid Association and European Thyroid Association guidelines for thyroid hormone 
replacement, due to a paucity of data from adequately designed studies.40,41 Well-designed 
studies are needed to test LT3’s potential clinical impact.  
 
Overt hyperthyroidism (low TSH with elevated free T4 or T3) and subclinical hyperthyroidism (low 
TSH with normal free T4 and T3) are each associated with an increased risk of atrial fibrillation.42-
44 Excess T3 from high doses of thyroid extract has been associated with increased cardiac 
symptoms.45 However, studies of combination LT4-LT3 therapy performed in over 1400 patients 
studied for 5 weeks to 12 months have not shown any increase in cardiac symptoms or events in 
patients taking combination therapy compared with standard LT4 therapy,40 nor has a small cross-
over study of complete replacement of LT4 for LT3.46 A Scottish registry study of 400 patients 
taking LT3 showed similar rates of atrial fibrillation and cardiovascular events to 33,955 patients 
taking LT4 therapy.47 Thus, although conditions of thyroid hormone excess increase risk of atrial 
fibrillation, data from studies and clinical practice do not support any increased arrhythmic risk 
from LT3 administration. This study will have careful monitoring of T3 levels, target levels within 
the reference range to prevent thyroid hormone excess, cardiac monitoring to detect any 
arrhythmic signal, and for the patients with HFrEF, ICDs in place.   
 
 
1.2.2.2   Proof of Concept Studies 
Proof of concept clinical studies using short-term intravenous LT3 infusions have 
demonstrated safety and efficacy in patients with heart failure. Though preclinical studies 
support the role of LT3 therapy in heart failure, little is known about the optimal route, dose, and 
frequency of LT3 therapy in humans. Clinical studies using short-term intravenous infusions of 
LT3, lasting a few hours to 3 days, show acceptable safety in patients without pre-existing thyroid 
dysfunction undergoing coronary artery bypass surgery and in heart failure.48-51 Hamilton et al 
administered a bolus followed by a 6 to 12 hour infusion of LT3 in 23 patients with HFrEF and 
showed increased cardiac output and decreased peripheral vascular resistance in 6 of 7 patients 
receiving the highest dose.50 Pingitore et al performed a 3 day infusion of LT3 (n=10) or placebo 
(n=10) in patients with HFrEF and showed improvements in N-terminal pro-B-Type natriuretic 
peptide, noradrenaline, and aldosterone in the LT3 group, along with an improvement in stroke 
volume, without changes in external and intracardiac workload.51 In both studies, LT3 was well 
tolerated without increased heart rate or arrhythmias. However, these studies were short-term, 
used intravenous LT3, and did not address HFpEF.  
1.3 
Dose Rationale (if applicable)  
Only one study has evaluated the effects of oral LT3 therapy, at a mean dose of 20 mcg daily 
(range 10-40 mcg) for 3 months, in 13 individuals who had low T3 syndrome and HFrEF with very 
mild reductions in ejection fraction at baseline (LV EF =43%).52 There was a non-statistically 
significant improvement in ejection fraction (43.3 vs. 46.0%; p=0.27) in this cross-over study, 
though it is arguable that ejection fraction was an appropriate primary endpoint for these patients. 
In addition, their twice daily dosing regimen and dependence on TSH levels instead of T3 levels 
for titration resulted in a small mean change in T3 levels (0.3 nmol/L; 20 ng/dL), which could have 
been insufficient to induce a meaningful physiologic effect. Cardiac monitoring for the first 48 

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hours did not detect any arrhythmias, and LT3 was well tolerated. A phase 2 study of the thyroid 
analog DITPA was halted early due to poor tolerance, despite improvements in cardiac index, 
systemic vascular resistance, cholesterol, and body weight.53 It is possible that too high a dose 
was selected for this study and that a dose ¼ of that used would have been tolerated while still 
achieving efficacy.  
 
These studies highlight the need for careful, individualized titration to stay within T3’s therapeutic 
window. 
 
We will be titrating LT3 to T3 levels, not TSH levels. The TSH level is a biomarker for pituitary 
sensitivity to T3, whereas the T3 assay is a direct measurement of circulating T3. At this time, 
there is no biomarker for cardiac tissue sensitivity to T3. The single published study of oral LT3 in 
HF titrated the LT3 dose to the TSH level, whereas the 3-day IV LT3 in HF study titrated LT3 dose 
to the T3 level.51,52 The 24-hour dose in the oral LT3 study was 2/3 of the dose in the IV LT3 study; 
only the IV LT3 study demonstrated a clinically meaningful difference. We will measure total T3 
levels from 2-4 hours after the LT3 dose, which represents the peak T3 level,54,55 to ensure that 
T3 level remains within the reference range throughout the day. There is little diurnal variation of 
endogenous T3, with only an 11% difference between peak and nadir levels.56 Endogenous peak 
T3 levels occur at approximately 4 am,56 which will not coincide with the peak T3 level from our 
planned evening LT3 dose. Within-person assessments of T3 levels are stable when assessed 
daily51 or monthly.57 Although, in theory, the free T3 assay should be more biologically relevant 
than the total T3 assay, measurement of pg/mL quantities of free T3 can be challenging. As such 
we will measure total T3, as recommended by the American Thyroid Association.58 
 
In this study, administration of liothyronine (LT3) will begin with an initial dose of 15 mcg daily. 
Dose titration of LT3 and matching placebo will be overseen by an unblinded study physician 
based on measured T3 levels.  Pharmacokinetic data suggest that 5 mcg three times daily should 
not result in T3 excess in patients with low endogenous T3 levels.54 The titration phase will be 
~four weeks, followed by a ~four week maintenance phase, before crossover.  There will be a 
~weekly titration of active drug and matched titration of placebo over ~four weeks based upon 
peak total T3 levels obtained 2-4 hours after the morning LT3 dose.  After ~four weeks of titration, 
the minimum LT3 dose will be 2.5 mcg three times daily (7.5mcg) and the maximum LT3 dose 
will be 12.5 mcg three times daily (37.5mcg), to be maintained for ~4 additional weeks. The ~2-
week washout between intervention periods will be of sufficient duration to metabolize exogenous 
LT3 due to the short half-life of LT3, which is less than a day.  The low initial dose described, 
gradual titration planned, and careful monitoring of T3 levels in addition to vigilant AE monitoring 
all will protect participants in relation to study dosing.   
 
2 
Study Objectives 
Our overall goal is to determine the safety, feasibility, and preliminary efficacy of oral LT3 therapy 
in patients with HF and low T3. We will assess the safety and preliminary efficacy of administering 
oral LT3 therapy in the two independent study populations in parallel: HFrEF and HFpEF. It is 
anticipated LT3 will be well tolerated without T3 excess, and that treatment with LT3 will show no 
evidence of increased AEs or arrhythmic events compared to placebo. We anticipate that 
secondary endpoints will provide sufficient estimates of effect size and variability in HF 
populations to enable accurate power calculations for future phase 2 trials focused on efficacy of 
LT3.  
 
 

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2.1 
Primary Objective 
 To determine the safety of oral LT3 therapy in heart failure with low T3 syndrome   
2.2 
Secondary Objectives 
 To determine the feasibility of oral LT3 therapy in heart failure with low T3 syndrome 
 To determine the preliminary efficacy of oral LT3 therapy in heart failure with low T3 
syndrome 
 To determine the plausible mechanistic pathways of LT3 effect 
 
3 
Investigational Plan  
3.1 
General Design 
The study is designed as two parallel randomized, double-blind, placebo-controlled cross-over 
studies with a ~2-week washout period between treatments (Figure 1). We will simultaneously 
investigate the safety, feasibility, and preliminary efficacy of thyroid hormone therapy (LT3) in 
individuals diagnosed with heart failure and low T3 syndrome: HFrEF individuals in one arm and 
HFpEF individuals in a second arm.  Within each group, each treatment period will be ~8 weeks 
in duration, with ~weekly titration of study drug for ~four weeks, followed by a maintenance dose 
for ~4 weeks, then ~2-week washout before crossing over to the other arm.  We will be titrating 
LT3 to T3 levels, measuring total T3 levels 2-4 hours after the LT3 dose.  
 
Figure 1. Study design 
 
The study drug will be dispensed in person at Visits 1 and 3. A pill cutter will also be provided at 
Visit 1. LT3 will be dosed three times daily to maintain stable levels.55 Liothyronine Sodium 
Tablets, USP in the 5 mcg dose and matching placebo tablets will be stored and dispensed from 
Penn’s IDS. 
 
The initial dose of LT3 started at Visit 1 will be 15 mcg (5 mcg three times daily: pre-breakfast, 
mid-afternoon, and bedtime). Six to nine days after initiation, the participant will go to a Penn-
affiliated laboratory for a peak total T3 measurement 2-4 hours after the morning dose. The 
following day, the unblinded study physician will call the participant to recommend continuing this 
dose if the total T3 level is >160 but <180 ng/dL (the upper limit of the reference range) vs. titration 
to 22.5 mcg (7.5 mcg three times daily) if the total T3 level ≤ 160 ng/dL. Pharmacokinetic data 
suggest that 5 mcg three times daily should not result in T3 excess in patients with low 
endogenous T3 levels.54 If the total T3 level is >180 ng/dL, the dose will be reduced to 7.5 mcg 

Developing Oral T3 for Heart Failure 
 
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(2.5 mcg three times daily), and the total T3 level will be rechecked the following week.  
 
The process of T3 assessment ~6 days after a dose change or confirmation and dose titration on 
the ~7th day will continue for an additional 3 weeks, to a maximum dose of 12.5 mcg three times 
daily. A titration in the placebo group will occur in parallel to LT3 titration. The titration phase will 
be ~4 weeks in duration, followed by a ~4-week maintenance dose phase.  After ~8 weeks, there 
will be a study assessment in the CHPS research unit (Visit 2). This will be followed by a ~two-
week washout and another assessment (Visit 3). Participants will cross-over and receive the 
alternate therapy, following the same titration scheme as in the initial ~8-week period and will 
undergo assessment in CHPS unit at Visit 4. Some flexibility (up to 3-day delays for titration 
assessments and up to 3 days before or after due dates for the maintenance dose and washout 
phases) will be allowed in the timing of these visits due to weekend, holidays, CHPS services 
availability, and/or participants’ personal circumstances.  
 
The primary safety outcomes will be T3 levels within range and arrhythmias. Additional testing at 
study visits include peak VO2, quality of life, NT-proBNP level, physical activity, 
echocardiography, tonometry measurements, resting energy expenditure, weight, and 
hyperthyroid symptoms. The length of active participation for each participant who qualifies for 
entry in the study will be ~19 weeks with a follow up phone call 1 week after Visit 4. 
 
3.1.1 Screening Phase 
Potential participants will be recruited from the University of Pennsylvania Health System’s three 
Philadelphia hospitals and affiliated outpatient practices.  We will use a 2-stage written informed 
consent process. A study team coordinator will pre-screen focusing on identifying potential study 
participants in general cardiology clinics, heart failure/transplant clinics, internal medicine clinics, 
and the echocardiography laboratory.  Potential participants who may fit criteria for enrollment 
based on record review will be consented for a screening TSH, free T4, and Total T3 blood test 
(See IRB # 833103 protocol/ICF for details).  Additionally, data about medical history, 
medications, and social habits may be collected at this time. They will be provided with a brief 
overview of the study and will be informed that if they qualify, we will approach them for a more 
detailed discussion later.  If they consent, the TSH, free T4, and total T3 will be obtained.  If they 
are eligible based upon this information, they will be scheduled for a Visit 1.      
 
3.1.2 Study Intervention Phase  
 
At the baseline study visit (Visit 1), the participant will be randomized to LT3 or placebo. Dose 
titration of LT3 and matching placebo will be overseen by an unblinded study physician based on 
measured T3 levels.  The initial dose of LT3 will be 15 mcg (5 mcg three times daily: pre-breakfast, 
mid-afternoon, and bedtime). At least six days (>6 half-lives of LT3) after initiation (range: 6-9 
days), the participant will go to a Penn-affiliated laboratory for a peak total T3 measurement 2-4 
hours after the morning dose. The following day, the unblinded study physician will call the 
participant to recommend continuing this dose if the total T3 level is >160 but <180 ng/dL (the 
upper limit of the reference range) vs. titration to 22.5 mcg (7.5 mcg three times daily) if the total 
T3 level ≤ 160 ng/dL. Pharmacokinetic data suggest that 5 mcg three times daily should not result 
in T3 excess in patients with low endogenous T3 levels. If the total T3 level is >180 ng/dL, the 
dose will be reduced to 7.5 mcg (2.5 mcg three times daily), and the total T3 level will be 
rechecked the following week. 
 

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The process of T3 assessment at least 6 days (range: 6-9 days) after a dose change or 
confirmation and dose titration on the 7th day will continue for an additional ~3 weeks, to a 
maximum dose of 12.5 mcg three times daily (37.5 mcg). A titration in a placebo participant will 
occur in parallel to each LT3 titration. The titration phase will be ~4 weeks in duration, followed 
by a ~4-week maintenance phase. 
 
After ~8 weeks, there will be a final study assessment on therapy in the CHPS research unit (Visit 
2). This will be followed by a ~two-week washout. Participants will have a repeat assessment at 
week 10 (Visit 3), cross-over, and receive the alternate therapy, following the identical titration 
scheme to the initial ~8-week period and a final assessment (Visit 4) at ~week 19. 
 
3.1.3 Follow Up Phase 
One week following Visit 4, a telephone follow-up call will be placed to assess for adverse events 
and answer any remaining participant questions regarding the study and intervention.   
3.1.4 Allocation to Interventional Group  
Study drug randomization and dispensing will be performed through the Penn Investigational Drug 
Service (IDS). A randomization list for the order of study drug administration (LT3 or placebo) will 
be created by the Investigational Drug Services (IDS) using a web-based program, separately for 
each arm (HFrEF and HFpEF).  Compliance with the randomization schemes for each study will 
be maintained by IDS in dispensing individual participant medication throughout the study. 
3.1.5 Primary Study Endpoints 
 
The primary study endpoints will be safety endpoints: Total T3 concentrations within upper limit 
of reference range (180 ng/dL); EKG assessment of arrhythmic events; cardiac monitoring 14 day 
adhesive patch electrocardiographic monitoring of arrhythmic events; and for the HFrEF arm only, 
ICD interrogation of arrhythmic events. 
 .   
The assessments below are required for assessment of LT3 safety  
 
Total T3 concentrations within upper limit of reference range (180 ng/dL)  
 
EKG assessment of arrhythmic events:  
 
Cardiac Monitoring14 day adhesive patch electrocardiographic monitoring of arrhythmic 
events  
 
ICD interrogation of arrhythmic Interrogation will occur after study completion (HFrEF only) 
3.1.6 Secondary Study Endpoints 
  
The secondary study endpoints will be preliminary efficacy endpoints: Peak oxygen consumption 
during a maximal effort exercise test (peak VO2); Quality of life (Kansas City Cardiomyopathy 
Questionnaire, KCCQ); Remotely sensed physical activity (actigraphy); NT-proBNP levels. 
 
The assessments below are clinically relevant efficacy outcomes: 
 
Peak oxygen consumption during a maximal effort exercise test (peak VO2) 
 
Quality of life (Kansas City Cardiomyopathy Questionnaire, KCCQ 
 
Remotely sensed physical activity (actigraph)  
 
NT-proBNP levels 
 
Mechanistic and Other secondary endpoints: 

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05/11/2022 
 
LV function, arterial load, and ventricular-arterial interactions via simultaneous Doppler 
echocardiography and arterial tonometry  
 
Resting energy expenditure  
 
Weight: At Visits 1-4, weight will be measured in the CHPS unit using a calibrated scale.  
 
ThyPRO questionnaire section for hyperthyroid symptoms:  
 
Thyroid function tests: Serum will be drawn for TSH, free T4, total T3, and reverse T3   
 
4 
Study Population and Duration of Participation 
4.1 
Major Inclusion Criteria 
 
HFrEF Inclusion  
1. Men and women aged ≥18 years  
2. NYHA Class I, II or III heart failure 
3. EF≤40 percent within the past year 
4. An implantable cardioverter-defibrillator (ICD)  
5. Stable doses of neurohormonal blockade for 30 days 
6. TSH of 0.27-5.33 mU/L and Free T4 level of 0.61-1.70 ng/dL and total T3 level <94 ng/dL 
7. If taking oral estrogen, dose must remain stable for duration of study participation.   
 
HFpEF Inclusion 
1. Men and women aged ≥18 years  
2. NYHA Class I, II or III heart failure or dyspnea on exertion without a clinically identifiable 
alternative cause 
3. LV EF40 percent 
4. If taking antihypertensive medications beta-blockers SGLT2 inhibitors, sacubitril/valsartan, 
or aldosterone antagonists, doses must be stable for at least 30 days 
5. Elevated filling pressures as evidenced by at least 1 of the following:  
a. Mitral E/e’ ratio > 14 (either lateral or septal) 
b. Mitral E/e’ ratio > 8 (either lateral or septal), with low e’ velocity (septal e’<7 
cm/sec or lateral e’< 10 cm/sec), in addition to one of the following: 
i. Enlarged left atrium (LA volume index >34 ml/m2)  
ii. Chronic loop diuretic use for control of symptoms 
iii. Elevated natriuretic peptides (BNP levels >100 ng/L or NT-proBNP 
levels >300 ng/L) 
iv. Tricuspid regurgitation velocity >2.8 m/s 
c. Elevated invasively-determined filling pressures previously (resting LVEDP>16 
mmHg or mean pulmonary capillary wedge pressure [PCWP] > 12 mmHg; or 
PCWP/LVEDP≥25 mmHg with exercise). 
d. Acute heart failure decompensation requiring IV diuretics within the past year 
e. Probability of HFpEF>90% according to the HFpEF score, without a more likely 
clinically apparent cause for symptoms, as per investigator assessment 
6. 
TSH of 0.27-5.33 mU/L and free T4 level of 0.61-1.70 ng/dL  level within the protocol 
specified reference range and total T3 level ≤0.94 ng/mL 
7.     If taking oral estrogen, dose must remain stable for duration of study participation.   
4.2 
Exclusion Criteria 
HFrEF Exclusion 

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1. 
Hypertrophic or restrictive cardiomyopathy or uncorrected severe primary valvular 
disease 
2. 
Arrhythmia that results in irregular heart rate 
3. 
Inability to perform VO2 max exercise testing 
4. 
Clinically significant lung disease as defined by: Chronic Obstructive pulmonary disease 
meeting Stage III or greater GOLD criteria 
5. 
Treatment with oral steroids within the past 6 months for an exacerbation of obstructive 
lung disease, or the use of daytime supplemental oxygen 
6. 
Serum creatinine > 3.0 mg/dL 
7. 
History of cirrhosis 
8. 
Chronic intravenous inotropic therapy 
9. 
LVAD use 
10. Heart failure hospitalization within the past month 
11. Acute coronary syndrome, coronary intervention, or ablation within the past 2 months 
12. Cardiac surgery or percutaneous valve or septal defect repair within the past six months 
13. Initiation of cardiac resynchronization therapy within the past six months 
14. Taking thyroid extract, LT4, LT3, amiodarone, or medication that affects the absorption or 
metabolism of thyroid hormone (see Appendix) 
15. Gastrointestinal condition that affects the absorption of thyroid hormone 
16. Current or planned pregnancy within the timeframe of study participation 
17. Any medical condition that, in the opinion of the investigator, will interfere with the safe 
completion of the study 
 
HFpEF Exclusion 
1. 
Hypertrophic or restrictive cardiomyopathy or uncorrected severe primary valvular 
disease 
2. 
Inability to perform VO2 max exercise testing   
3. 
Clinically significant lung disease as defined by: Chronic Obstructive pulmonary disease 
meeting Stage III or greater GOLD criteria 
4. 
Treatment with oral steroids within the past 6 months for an exacerbation of obstructive 
lung disease, or the use of daytime supplemental oxygen 
5. 
Serum creatinine > 3.0 mg/dL 
6. 
History of cirrhosis 
7. 
Heart failure hospitalization within the past month 
8. 
Acute coronary syndrome or coronary intervention within the past 2 months 
9. 
Cardiac surgery or percutaneous valve or septal defect repair within the past six months 
10. Taking thyroid extract, LT4, LT3, amiodarone, or medication that affects the absorption or 
metabolism of thyroid hormone (see Appendix). 
11. Gastrointestinal condition that affects the absorption of thyroid hormone 
12. Current or planned pregnancy within the timeframe of study participation   
13. Any medical condition that, in the opinion of the investigator, will interfere with the safe 
completion of the study. 
 
4.3 
Participant Recruitment  
 
We will leverage an existing recruitment pipeline for heart failure study participants currently used 
by the Cardiovascular Clinical Research Unit (CCRU). Potential participants will be recruited from 
the University of Pennsylvania Health System’s three Philadelphia hospitals which operate under 
a single Penn IRB.  Depending on effectiveness, the following recruitment modalities may be used 

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05/11/2022 
for this study and / or utilizing a telephone recruitment script: 
 
1. Screening and approaching participants who have previously participated in HF and/or 
aging studies and have expressed interest in continuing engagement with new protocols.   
2. Direct Advertising including postings on the Cardiovascular Medicine Divisional website, 
clinics, and cardiovascular clinical laboratories, postings to be approved.   
3. Outpatient Clinic Recruitment: General cardiology clinics, HF clinics, echocardiography 
laboratory, clinical stress testing laboratory  
4. Inpatient clinical service with treating physician approval 
5. Real-time participant identification through Penn Chart in the form of Best Practice 
Advisories (pop-ups).  Once identified, team coordinators can approach these potential 
candidates with physician approval to provide study information for consideration.    
6. Agent Insights identification with telephone or clinic approach utilizing an approved 
telephone script.    
 
Persons who are unlikely to complete study visits due to non-compliance, lack of social support, 
psychiatric illness or major comorbidities, substance abuse, or other social or logistic 
circumstances will be evaluated on a case-by-case basis.  
 
4.4 
Duration of Study Participation 
Screening for participants will require a blood test and review of other medical records and tests. 
Scheduling the next visit for those that qualify may take up to 4 weeks. Active participation after 
screening will be ~19 weeks with a ~1-week follow-up phone call after the final visit.   
4.5 
Total Number of Participants and Sites  
Recruitment will end when 56 enrolled participants (28 HFrEF, 28 HFpEF) are randomized. It is 
expected that 280 participants will undergo informed consent procedures.  
4.6 
Vulnerable Populations  
 
Pregnant women or women planning to become pregnant will be excluded. Children younger than 
18 will not be included because the prevalence and consequences of low T3 syndrome in children 
with heart failure are not known.  In addition, insufficient data are available undermining the ability 
to judge potential risk in children. No other special vulnerable populations will be enrolled. All 
participants will be able to provide informed consent.   
 
5 
Study Intervention  
5.1 
Description 
The Investigational product is Liothyronine (L-triiodothyronine or LT3) is a synthetic form of the 
natural thyroid hormone triiodothyronine (T3), available as a sodium salt.  We will be using the 5 
mcg tablet formulation and a matching placebo for this intervention.  Liothyronine Sodium Tablets, 
USP in the 5 mcg dose and matching placebo will be obtained from Sigmapharm Laboratories 
and delivered to Kenneth Rockwell, PharmD, MS, Director of Penn’s Investigational Drug Service. 
 
Study Drug and Randomization: Study drug randomization and dispensing will be performed 
through the Penn Investigational Drug Service (IDS). A randomization list for the order of study 
drug administration (LT3 or placebo) will be created by the IDS using a web-based program, 

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separately within each study arm - HFrEF and HFpEF. All study drug will be prepared and 
dispensed by IDS pharmacy.  The drug will be delivered directly to the participant at Visits 1 and 
3.  A pill cutter will be provided at Visit 1 so that the scored tablets can be cut according to titration 
instruction by the unblinded study physician.   
 
5.2 
Study Intervention Regimen 
Study Drug Intervention: Oral LT3 or matched placebo will be self-administered three times daily 
by participants. There will be a weekly titration of active drug/placebo for four weeks based on 
weekly peak total T3 levels overseen by an unblinded study physician.  The T3 levels will be 
obtained 2-4 hours after the morning LT3 dose. Based upon the T3 result, the unblinded study 
physician will call the participant with specific dosing instructions to follow immediately throughout 
the coming week.  After four weeks of titration in this manner, the minimum LT3 dose will be 2.5 
mcg three times daily and the maximum LT3 dose will be 12.5 mcg three times daily. This dose 
will be continued for an additional four-week maintenance phase during which weekly T3 levels 
are not required and the dose will remain steady for these four weeks. After a two-week washout, 
the participants will cross-over and receive the alternate therapy, following the identical titration 
scheme to the initial 4-week period with another 4-week dose maintenance phase. 
5.3 
Receipt  
Upon receipt of the drug supply or placebo, an inventory will be performed by the IDS and a drug 
receipt log filled out and signed by the IDS staff person accepting the shipment. The designated 
study staff will count and verify that the shipment contains all the items noted in the shipment 
inventory. Any damaged or unusable study drug in a given shipment will be documented in the 
study files. 
5.4 
Storage 
Liothyronine 5 mcg tablets and placebo will be stored at room temperature in a dry place. They 
will be kept securely within the IDS pharmacy in a location protected from light and from excess 
heat or moisture.   
 
5.5 
Preparation and Packaging 
The preparation, labeling and dispensing of all study drug (LT3 and placebo) will be done by the 
IDS Pharmacy (available at 215-349-8817 or, for after-hours emergencies, 800-670-3151) in 
accordance with HUP’s Pharmacy Policy and Procedures. Each drug label will include the 
participant’s unique identification number, date dispensed, and directions for use.  The study drug 
ordered for each participant will be delivered individually by IDS to that participant during study 
visits 1 and 3 in the CHPS Unit and collected and returned to IDS during study visits 2 and 4. 
 
5.6 
Blinding 
Study drug randomization will be performed through the Penn Investigational Drug Service (IDS). 
A randomization list for the order of study drug administration (LT3 or placebo) will be created by 
the IDS using a web-based program, separately for each of the two study arms. The IDS will 
subsequently perform randomization assignment, and all study investigators, staff, and 
participants will be masked to treatment vs. placebo assignment. Group assignments will be kept 
confidential by IDS in order to maintain study blinding. Unblinding will be strongly discouraged 
and will occur only in the event of an emergency where knowledge of the treatment assignment 
would affect clinical care, or if recommended by DSMB and/or IRB to address safety concerns. 

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Otherwise, unblinding will occur only after the study is complete, data collection is complete, and 
the database is locked. 
   
5.7 
Administration and Accountability    
 
Study drug will be dispensed in person at Visits 1 and 3 by the IDS.  A pill cutter will be provided 
to each participant at Visit 1. Sufficient medication for an 8-week period with titrations will be 
dispensed. LT3 will be dosed three times daily to maintain stable levels.55  
 
The initial dose of LT3 will be 15 mcg (5 mcg three times daily: pre-breakfast, mid-afternoon, and 
bedtime). At least six days (range: 6-9 days) after initiation, the participant will go to a Penn-
affiliated laboratory for a peak total T3 measurement 2-4 hours after the morning dose. The 
following day, the unblinded study physician will call the participant to recommend continuing this 
dose if the total T3 level is >160 but <180 ng/dL (the upper limit of the reference range) vs. titration 
to 22.5 mcg (7.5 mcg three times daily) if the total T3 level ≤ 160 ng/dL. Pharmacokinetic data 
suggest that 5 mcg three times daily should not result in T3 excess in patients with low 
endogenous T3 levels.54 If the total T3 level is >180 ng/dL, the dose will be reduced to 7.5 mcg 
(2.5 mcg three times daily), and the total T3 level will be rechecked the following week. 
 
The process of T3 assessment 6-9 days after a dose change or confirmation and dose titration 
on the 7th day will continue for an additional 3 weeks, to a maximum dose of 12.5 mcg three times 
daily. A titration in the placebo group will occur in parallel to LT3 titration. The titration phase will 
be 4 weeks in duration, followed by a 4-week maintenance phase. 
 
After those ~8 weeks, there will be a study assessment in the CHPS research unit (Visit 2). This 
will be followed by a ~two-week washout and another assessment (Visit 3). Participants will cross-
over and receive the alternate therapy, following the identical titration scheme to the initial ~8-
week period and assessment at Visit 4.  
 
5.8 
Participant Compliance Monitoring 
 
Adherence will be assessed by direct questioning of study participants during weekly telephone 
follow-up and study visits. Any evidence of noncompliance will be recorded and participants who 
are significantly noncompliant with the study treatment regimen may be withdrawn from the study. 
Determination of noncompliance will be based on investigator judgment. To avoid unnecessary 
adjustments, un-blinded study physician involved in any medication adjustments will be made 
aware by study team members of the participants’ self-reported adherence to the regimen. Study 
drug will be collected by IDS at participant study visits 2 and 4 and drug reconciliation will be 
performed to document drug assigned, drug consumed, and drug remaining. This reconciliation 
will be logged, signed and dated by the IDS and retained in their records. 
 
5.8.1 Return or Destruction of Investigational Product 
 
At the completion of the study, there will be a final reconciliation of drug distributed, drug 
consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, 
signed and dated in the IDS pharmacy.  Drug destroyed on site will be documented in the study 
files. 

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6 
Detailed Study Procedures 
 
Clinical Evaluation:  Visits 1-4.  At each visit, a study physician, nurse or delegated study staff 
will complete a physical exam and review medical history/interim medical history. Vital signs 
including height (Visit 1 only), weight, blood pressure, heart rate, pulse ox, and respiration rate 
will be measured.  Current medication and changes to medications since prior visit will be 
recorded.   
  
Resting Energy Expenditure (REE): Visits 1-4. REE will be obtained by indirect calorimetry 
using the ventilated hood technique (ParvoMedics, Sandy, UT). 
 
EKG: Visits 1-4. 12-lead EKGs will be obtained using the GE Mac 5500 and stored digitally in the 
MUSE system. EKGs will be read by study investigators blinded to patient and treatment 
assignment. Variables of interest include heart rate, rhythm, measures of conduction (PR and 
QRS intervals) and repolarization (QT, QTc). 
 
Echocardiography and Arterial Tonometry: Visits 1-4. Participants will undergo simultaneous 
Doppler echocardiography and arterial tonometry to assess LV function, arterial load and 
ventricular-arterial interactions. Both noninvasive assessments are routinely performed in the 
CHPS unit. From this brief assessment, an array of physiologic measures can be derived after 
data acquisition, as described below.  
 
Transthoracic echocardiography will be performed using a Vivid I e9 system (General Electric). 
The protocol will include standard 2D imaging, pulsed-wave Doppler interrogation of LV inflow 
and outflow tract velocities, and tissue-Doppler interrogation of mitral and tricuspid annular 
velocities. Simultaneous to LV outflow tract Doppler interrogation, radial and carotid applanation 
tonometry will be performed using a commercially available system (SphygmoCor EM3, AtCor 
Medical) with a high-fidelity applanation tonometer (Millar Instruments).59 Brachial arterial 
pressures will be measured with a validated oscillometric device (Omron 705IT/HEM-759-E; 
Omron Healthcare).60 Radial waveforms will be calibrated with brachial systolic and diastolic 
pressures. Radial pressures will be used to calibrate the carotid pressure waveform, which serves 
as a surrogate of the central pressure waveform.61 Once these data are acquired, the following 
offline analyses will be performed to generate quantitative physiologic readouts: 
LV diastolic function: We will quantify LV diastolic function using the early diastolic (e') mitral 
annular velocity, averaged from septal and lateral annular measurements.62 The ratio of mitral 
inflow early diastolic velocity to mitral annular velocity (E/e’) will be used as an indicator of LV 
filling pressures.  
LV myocardial strain: We will quantify peak longitudinal myocardial strain using echoPAC speckle-
tracking software (GE Healthcare).63-66   
Arterial wave reflections and ventricular-arterial interactions: We will implement detailed analyses 
of arterial pulsatile load using custom-designed software in Matlab (R2011b, MathWorks, Natick, 
MA) as previously described.61,67-69 After signal-averaging of pressure and flow waveforms, time 
alignment of carotid pressure and LV outflow signals will be performed.61 Pressure and flow 
harmonics will then be separated into forward and backward components using wave separation 
analysis.61,67-69 The sum of forward and backward pressure harmonics yields the forward and 
backward waves, respectively. Reflection magnitude (RM) will be computed as the ratio of 
backward to forward wave amplitudes (Pb/Pf).  
 

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Kansas City Cardiomyopathy Questionnaire (KCCQ): Visits 1-4. This is a validated 23-item 
questionnaire that assesses physical function, symptoms, social function, self-efficacy and 
knowledge, and quality of life.70 It has been used extensively in multiple heart failure studies. 
 
Hyperthyroid Symptoms from the Thyroid-specific Patient Reported Outcome Measure 
(ThyPRO): Visits 1-4. This is a validated, thyroid-specific quality of life instrument with 13 
scales.71-73 We will administer 8 items from the Hyperthyroid scale.   
 
Laboratory Assessments: Visits 1-4. Non-fasting venous bloods will be drawn, processed, and 
stored at -80 degrees for future batched performance of TSH, free T4, total T3, reverse T3, and 
NT-ProBNP at the Penn Diabetes Research Center Radioimmunoassay and Biomarkers Core. 
At this time, we plan to use the Cobas 4000 analyzer (Roche Diagnostics, Indianapolis, IN) for 
TSH, free T4, total T3, and NT-proBNP assays and an ALPCO kit for reverse T3.  However, 
assays change over time, and we will use the best commercially available assays in Year 4 for 
batched analysis. 
 
Cardiac Monitoring Device Monitor: The cardiac monitoring device is a one channel, two-lead 
cardiac monitor that will provide continuous ECG recording up to 14 days (Figure 2). Since the 
device is small and lightweight (<1 oz.) and does not require battery changes 
for the duration of monitoring, patient compliance and comfort level is high. 
A monitor will be placed at Visits 1 and 3, and participants will be asked to 
wear the monitor for the first two weeks of each study period. The data are 
collected for the entirety of the 14 days and are downloaded when the 
monitors are returned. The data are then analyzed and a summary report 
generated. This report will be reviewed by Dr. David Lin, electrophysiologist 
and co-investigator on this protocol, in a blinded fashion. Dr. Lin will also 
review ICD interrogation data collected during the 17week study period, in a 
blinded fashion.  
 
Actigraph wGT3X+ Waist Actigraph: We will use waist actigraphy.  The units are the 
size of a large wristwatch (Figure 3) and are attached to an elastic belt worn around the 
waist.   Participants will be asked to wear the unit for the last two weeks of each study 
period (before Visits 2 and 4) except when bathing or charging the unit. The CHPS 
mHealth service will provide and support the wGT3X+ (maintenance, data downloads, 
etc.).  Activity counts will be recorded in 10 second epochs, downloaded wirelessly, and 
analyzed using ActiLife software. A Counts per Minute (CPM) value will be derived. 
 
Peak VO2: Visit 2, 4. Participants will perform a maximal effort supine bicycle exercise 
test in conjunction with expired gas analysis to assess oxygen consumption (VO2) during 
exercise, using a Parvo Medics True One 2400 device. We will use a supine cycle ergometer 
designed for stress echocardiography (Stress Echo Ergometer 1505, Medical Positioning, Inc, 
Kansas City, MO) and a graded-exercise protocol, with resistance beginning at 12.5 W for 3 
minutes, increasing to 25 W for 3 minutes, and then increasing by 25 W every 3 minutes 
thereafter.  
 
 
 
Figure 3. Actigraph. 
Figure 2. Example 14 day monitor 

Developing Oral T3 for Heart Failure 
 
Page 19 
 
 
05/11/2022 
6.1 
Schedule of Assessments 
Study 
Visit 1 
(Baseli
ne) 
 
 
 
 
 
Stud
y 
Visit 
2 
Wash
-out 
Stud
y 
Visit 
3 
 
 
 
 
 
Study 
Visit 
4 
Week No.  
0 
1 
2 
3 
4 5-7 
8 
10 
1
1
1
2
13 
14-17 18 
19 
Study Drug Dose 
(LT3 
versus
placebo) 
0 
mcg 
5 
µg 
TID
2.5-
7.5 
µg 
TID
2.5-
10 
µg 
TID
2.5-
12.5 
µg 
TID* 
2.5-
12.5 
µg 
TID* 
2.5-
12.5 
µg 
TID* 
No 
drug 
No 
drug 
5 µg 
TID 
2.5-
7.5 
µg 
TID
2.5-
10 
µg 
TID*
2.5-
12.5 
µg 
TID* 
2.5-
12.5 
µg 
TID* 
2.5-
12.5 
µg 
TID* 
Visit 
In-person (CHPS)
X 
X 
      X 
X 
Informed Consent
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Lab  
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
Phone(complianc
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
X 
Clinical 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim 
Medical
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
     
Physical 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
     
12-lead ECG 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Laboratory 
Banked** 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
Local: Total T3 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Primary 
Peak V02 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Secondary 
Transthoracic 
X 
X 
   X 
X 
Arterial tonometry 
X 
X 
   X 
X 
Rest 
X 
X 
   X 
X 
Actigraphy 
-
 
    
X 
 
    
X 
 
KCCQ** 
X 
X 
   X 
X 
ThyPRO 
X 
X 
   X 
X 
14 
day 
rhythm
+ 
X 
X 
^
+ 
X 
X 
^
Study Drug  
Dispense 
Study
Drug 
X 
 
! 
  X 
 
      ! 
* Maximum dose tolerated 
** NT-pro-BNP, TSH, free T4, total T3 and reverse T3 
*** Kansas City Cardiomyopathy Questionnaire 
+ Cardiac monitoring device placed ^ Cardiac monitoring device collected 
! Medication Collected 
 
6.2 
Study Intervention Visits 
 
Initial contact: (-4 Week-0 Week), the participant reviews and signs a screening consent form for 
an eligibility blood draw (under protocol # 833103) for TSH, free T4, and Total T3 and to collect 
additional data about medical history, medications, and social habits. Once eligibility is 
established, the participant will be scheduled for visit 1. In person study visits 1-4 will occur in the 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
Center for Human Phenomic Sciences (CHPS) outpatient unit.   
 
Baseline/Visit 1: The participant will review and sign the full IRB-approved consent form with the 
study PI or CoI. A urine pregnancy test will be performed in women with child-bearing potential. 
A study physician or CHPS nurse practitioner will perform a physical examination including 
medical history. Weight and vital signs will be measured, current medications discussed, and 
resting energy assessment will be performed, followed by EKG, echocardiogram, and tonometry. 
Participants will complete the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 
Hyperthyroid Symptoms from the Thyroid-specific Patient Reported Outcome Measure (ThyPRO) 
questionnaires. Approximately 2 teaspoons of venous blood will be collected for NT-pro-BNP, 
TSH, T4, Total T3, and Reverse T3, processed, and stored at -80 degrees. Participants will 
receive verbal and written instructions on dosing, a pill-cutter, and sufficient study medication for 
8 weeks.  A 14-day rhythm monitoring patch will be applied to wear home. They will also be 
provided with a schedule of the lab testing for T3 levels they are required to obtain over the next 
four weeks, dates for study visits 2, 3 and 4 with all planned study procedures displayed.  
Participants will be mailed a pre-programmed Actigraph and belt with instructions to place 14 days 
before visit 2.  Study staff will cue them to place at that time during telephone call. Study 
medication will be dispensed and pill cutter will be provided.    
 
Interim dose titration (Weeks 1-4): Dose titration will be managed by an unblinded study physician, 
using the titration protocol to achieve a peak T3 level in the upper portion of the reference range.  
The initial dose of LT3 will be 15 mcg (5 mcg or 1 tablet three times daily: pre-breakfast, mid-
afternoon, and bedtime). Six to nine days (>6 half-lives of LT3) after initiation, the participant will 
be instructed to go to a Penn-affiliated laboratory for a peak total T3 measurement 2-4 hours after 
their morning dose. The following day, the unblinded study physician will call the participant to 
recommend continuing this dose if the total T3 level is >160 but <180 ng/dL (the upper limit of the 
reference range) vs. titration to 22.5 mcg (7.5 mcg or 1 ½ tablet three times daily) if the total T3 
level ≤ 160 ng/dL.  If the total T3 level is >180 ng/dL, the dose will be reduced to 7.5 mcg (2.5 
mcg or ½ tablet three times daily), and the total T3 level will be rechecked the following week. 
The unblinded study physician and study staff (during telephone follow-up) will instruct regarding 
pill cutting, and specifically explain the physical quantity of medication participant should take for 
the week each time a dose is revised. The process of T3 assessment 6-9 days after a dose 
change or confirmation and dose titration on the ~7th day will continue for an additional ~3 weeks, 
to a maximum dose of 37.5 mcg (2 ½ tablets three times daily). A titration in the placebo group 
will occur in parallel to LT3 titration. The titration phase will be ~4 weeks in duration, followed by 
a ~4-week maintenance phase. Participants will be called the day before each lab visit to assess 
symptoms, be reminded about the blood draw, and verify study medication dosing. At the day 13 
call, they will be reminded to remove the monitoring patch on day 14, to be returned at visit 2.   
 
Weekly calls (Weeks 5-8): Participants will be called weekly to assess symptoms and verify 
medication compliance. They will be reminded to start wearing the Actigraph attached to the belt 
over or under their clothing 2 weeks prior to study visit 2.  
 
Visit 2: (~Week 8): Participants will repeat all measures from Visit 1 plus peak VO2 to assess the 
effects of their first study medication. They will return the cardio key rhythm monitoring patch, 
actigraph, and remaining study medication, which will be collected by IDS for a pill count.  
Actigraph data will be downloaded by designated CHPS staff. Participant will be instructed of two-
week medication wash-out, and visit 3 date will be confirmed. 
 
Visit 3 (~Week 10): After a two-week washout, participants will repeat all measures from Visit 1.  
They will cross-over to the second preparation of study medication (LT3 or placebo) sufficient for 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
~8 weeks which will be provided to participant by IDS.  Participants will once again receive verbal 
and written instructions on dosing and schedule of lab testing for T3 levels required over the next 
four weeks. They will repeat interim dose titrations as described for weeks ~1-4 during weeks 
~10-14. A 14-day rhythm monitoring patch will be applied. Participants will be provided with a pre-
programmed actigraph and belt with instructions to place 14 days before visit 4, assuring study 
staff will cue them to place at that time.  
 
Weekly calls (~Weeks 10-14): Participants will be called weekly to assess symptoms and verify 
medication compliance. They will be reminded to start wearing the Actigraph attached to the belt 
over or under their clothing 2 weeks prior to study visit 4. 
 
Visit 4 (~Week 18): Participants will perform all measurements from visit 1 plus peak VO2 to 
assess the effects of their second study medication. They will return the cardio key rhythm 
monitoring patch, Actigraph, and remaining study medication, which will be collected by IDS for a 
pill count.  Actigraph data will be downloaded.  Participant will be instructed of follow-up call they 
will receive at week ~19 and confirmed they have retained the emergency contact number for the 
study.   
 
Follow-up call (~Week 19): Participants will be called to assess for signs and symptoms of 
adverse events and to respond to any questions regarding the study and their care related to it.   
 
6.3 
Participant Withdrawal  
The protocol defined follow-up period per participant will be up to ~19 weeks + 4 weeks from 
the initial screen. A participant may withdraw from the study for unanticipated reasons.   
 
If there is a participant withdrawal for any reason, clear documentation in the participant CRF’s 
will reflect the circumstance and any follow-up required or recommended by Study 
Investigator(s).  Participants who withdraw early will be requested to attend one final visit to 
collect investigational product and to follow up regarding adverse events.    
6.3.1 Data Collection and Follow-up for Withdrawn Participants 
Attempts will be made to obtain at least survival data on these participants up to the end of the 
participant follow-up period. In the case where the participant withdraws consent from 
participation in the study, permission to collect survival data will be obtained first. A participant 
will be labeled as “Lost to Follow-Up” only after the following has been documented: 
 
1. Failure to reach the participant by telephone on 3 separate days 
2. Failure to reach the participant’s next of kin on 3 separate days 
3. Failure to ascertain participant status via direct electronic medical record consultation.  
 
6.4 
Early Termination Visits   
The protocol defined follow-up period per participant will be up to 19 weeks + time from initial 
screen. A participant may be withdrawn from the study prior to his or her expected completion 
date for the following reasons: 
 
1. If the investigator discovers a condition(s) which indicates unacceptable risk to the 
participant 
2. If the participant fails to adhere to the protocol requirements 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
3. If the participant withdraws consent from participation in the study 
 
If there is a participant early termination for any reason, clear documentation in the participant 
CRF’s will reflect the circumstance and any follow-up required or recommended by Study 
Investigator(s).  For participants who are withdrawn early, every attempt will be made to 
schedule one final visit to collect investigational product and to follow up regarding adverse 
events.    
7 
Statistical Plan 
This is an early phase study, and thus our primary outcome is safety, defined by T3 levels and 
arrhythmias via rhythm monitoring. Our secondary outcomes are defined as efficacy, 
mechanistic, and other. We have not pre-specified a primary efficacy outcome, as we have not 
powered our study for efficacy. Instead, we will obtain estimates of central tendency and 
variance for efficacy to use to power a larger study, as long as the safety parameters support 
advancing to a larger study. Our other outcomes include clinically relevant efficacy outcomes 
(peak rate of oxygen consumption [VO2], quality of life and HF symptoms scores, home activity 
measured via actigraphy, and NT-proBNP) and mechanistic outcomes (noninvasive 
assessments of left ventricular function, vascular function, ventricular-arterial coupling, resting 
energy expenditure, and weight). We will also collect data on hyperthyroid symptoms and 
thyroid function testing. Each outcome is listed in Table 1 below, along with data collection 
instrument, type of variable, measure, and psychometric properties. 
 
Table1  Safety and Efficacy Outcomes  
Outcomes 
Instrument/Source 
Type 
Measure 
Properties  
Safety 
T3 levels  
N/A 
Discrete 
% of participants 
with T3 level above 
upper limit of 
reference range 
(180 ng/dL) at 8  
weeks 
N/A 
Rhythm 
monitoring 
EKG 
Continuous 
and 
Discrete 
Heart rate, rhythm, 
PR and QRS 
intervals, QT, QTc 
 
Rhythm 
monitoring  
Cardiac monitoring device 
14-day ECG recording 
Continuous 
and 
Discrete 
% of time in afib, # 
of VT episodes, # of 
supraventricular and 
ventricular ectopic 
episodes  
N/A 
Rhythm 
monitoring 
ICD interrogation data 
Discrete 
Arrhythmias 
detected 
N/A 
 
Secondary (Efficacy) 
Peak VO2 
Parvo Medics True One 2400 
device 
Continuous Peak rate of oxygen 
consumption  
N/A 
Quality of Life 
Validated 23-item Kansas City 
Cardiomyopathy Questionnaire 
(KCCQ)70 
Scale 
Each item is rated 
on a 1-5 Likert 
scale. Scale scores 
are transformed to a 
Cronbach’s α: 
0.62-0.90 
across 5 
domains 

Developing Oral T3 for Heart Failure 
 
Page 23 
 
 
05/11/2022 
0 to 100 range by 
subtracting the 
lowest possible 
scale score, dividing 
by the range of the 
scale and 
multiplying by 100. 
 
8-week 
change NS* 
using a paired 
t-test 
 
Home activity   
wGT3X+ actigraph unit series 
(ActiGraph, LLC)  
Continuous 
Physical activity in 
counts per minute 
(CPM) 
N/A 
NT-proBNP 
Serum immunoassay, Cobas 4000 
analyzer 
Continuous Pg/mL 
Analytic 
range  
5‑35,000  
 
Secondary Mechanistic and Other 
Echocardiography 
and arterial 
tonometry 
Transthoracic echocardiography 
will be performed using a Vivid I 
system (General Electric). 
Tonometry will be performed using 
a commercially available system 
(SphygmoCor EM3, AtCor Medical) 
with a high-fidelity applanation 
tonometer (Millar Instruments)   
Continuous 
Integrated measures 
of ventricular and 
vascular function 
N/A 
Resting energy 
expenditure 
(REE) 
Ventilated hood technique 
(ParvoMedics, Sandy, UT) 
Continuous Indirect calorimetry 
N/A 
Weight 
Standing, calibrated scale 
Continuous Kg 
N/A 
Hyperthyroid 
Symptoms 
8 hyperthyroid symptoms 
(validated) from the Thyroid-
specific Patient Reported Outcome 
(ThyPRO) Measure Questionnaire 
Section71-73 
Scale 
Each item is rated 
on a 0-4 Likert 
scale. The average 
score of items in a 
scale is divided by 
four and multiplied 
by 100 to yield a 0-
100 scale, with 
higher scores 
indicating 
worse health status. 
Cronbach’s α: 
0.89 
 
Intra-class 
correlation 
coefficient 
(ICC): 0.89 
(0.82-0.93) 
Thyroid function 
tests 
Serum immunoassay, Cobas 4000 
analyzer 
ELISA, ALPCO kit (rT3) 
Continuous 
 
TSH: IU/L 
Free T4: ng/Dl 
Total T3: ng/mL 
rT3: ng/mL 
Analytic 
range 
TSH: 0.005-
100  
Free T4: 
0.10-7.77 
Total T3: 
19.5-651 
rT3: 0.02-2 
* NS=Not significant  
 
 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
7.1 
Primary Endpoint 
This is an early phase study, and thus our primary outcome is safety, defined by T3 levels and 
arrhythmias via rhythm monitoring (rhythm monitoring and % of participants with T3 levels 
above the reference range (180 ng/dL) at the completion of each drug).  
 
7.2 
Secondary Endpoints  
Clinically relevant efficacy outcomes: 
 
Peak oxygen consumption during a maximal effort exercise test (peak VO2) 
 
Quality of life (Kansas City Cardiomyopathy Questionnaire, KCCQ 
 
Remotely sensed physical activity (actigraph)  
 
NT-proBNP levels 
 
Mechanistic and other secondary endpoints: 
 
LV function, arterial load, and ventricular-arterial interactions via simultaneous Doppler 
echocardiography and arterial tonometry  
 
Resting energy expenditure  
 
Weight: At Visits 1-4, weight will be measured in the CHPS unit using a calibrated scale.  
 
ThyPRO questionnaire section for hyperthyroid symptoms:  
 
Thyroid function tests: Serum will be drawn for TSH, free T4, total T3, and reverse T3   
7.3 
Statistical Methods 
Preliminary Analyses and Descriptive Statistics: Preliminary data analyses will include 
estimating descriptive statistics for all baseline measures to characterize the sample from which 
subsequent inferences may be drawn. Descriptive statistics will include measures of central 
tendency (mean, median, mode) and variation (standard deviation, interquartile range, range) 
for continuous measures. Distributional properties of all variables will be examined to determine 
if variance stabilizing or normalizing transformations should be applied. For dichotomous and 
categorical variables, measures will include frequencies and percentages. Interim quality 
analyses will be performed regularly to ensure that data collection and archiving procedures are 
operating correctly. Descriptive estimates of all measures will be generated for all enrollees at 
each of the observed time points or period, as well as by intervention group within each time 
point. Outliers will be accessed via visual inspection of distributions and checked for accuracy. 
The intervention groups will initially be compared within each period, with time invariant 
covariates only compared for period 1, according to continuous covariates using parametric or 
non-parametric two-sample t-tests within the general linear modeling framework, depending 
upon whether or not normality appears to be in question. Levine’s tests will be used to assess 
homogeneity of variance, and normality will be assessed using Shapiro-Wilk tests. Should 
violations emerge, transformations will be applied or the non-parametric Wilcoxon test will be 
performed. Additionally, the intervention groups will be compared within period according to 
categorical covariates using Fisher’s Exact tests. Significant differences between groups on 
these variables will result in their use as control variables in the modeling of outcome.   
 
Primary Analyses - This study will utilize a crossover design, such that 28 patients with HFrEF 
and 28 patients with HFpEF will be enrolled and randomized to one of 2 sequences, each of 
which consists of 2 periods (AB/BA design, where A=treatment and B=placebo). Specifically, 
within each of the two patient groups (HFrEF and HFpEF), 14 participants will be randomized to 
8 weeks of placebo, two week washout, followed by 8 weeks of treatment (BA), and 14 
participants will be randomized to 8 weeks of treatment, two week washout, followed by 8 
weeks of placebo (AB). See Table 2 below for more details. Peak VO2 and actigraphy will be 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
examined after placebo and after treatment (two timepoints only; TP2 and TP4). All other 
outcomes will be assessed before and after placebo and before and after treatment (4 
timepoints; TP1-TP4).  
 
The primary outcome is safety (rhythm monitoring and % of participants with T3 levels above 
the reference range at the completion of each drug). We will be monitoring and summarizing 
safety data using descriptive statistics. Rhythm monitoring will be described using measures of 
central tendency and variation, as well as frequencies and percents. Frequencies and percents 
will be used to describe participants with T3 levels above the upper limit of reference range at 
the completion of each drug. We will not have separate criteria for stopping by the DSMB. We 
will also be reporting the number of dropouts/discontinuations as well as the reasons for 
dropouts/discontinuations.  
 
Table 2. Study Design Overview 
HFrEF patients (n=28) 
BA Arm (n=14) 
Phase 1: 8 weeks of placebo  2 week washout  Phase 2: 8 weeks of treatment 
AB Arm (n=14) 
Phase 1: 8 weeks of treatment  2 week washout  Phase 2: 8 weeks of placebo 
HFpEF patients (n=28) 
BA Arm (n=14) 
Phase 1: 8 weeks of placebo  2 week washout  Phase 2: 8 weeks of treatment 
AB Arm (n=14) 
Phase 1: 8 weeks of treatment  2 week washout  Phase 2: 8 weeks of placebo 
TP1=week 0; TP2=week 8; TP3=week 10, TP4=week 18 
 
The legitimacy of the two week washout period will be evaluated by comparing week 0 (TP1) 
versus week 10 (TP3) outcome measures within the AB/BA arms for each of the two patients 
groups. If the outcome measures are within 20% of one another, a clinically significant 
difference, then we will conclude that the two week washout period is legitimate and we will use 
data from both phases of both arms (AB and BA) in our estimates of outcomes and effect sizes. 
If the difference between the outcome measures exceeds 20%, then we will conclude that the 
two week washout period is not legitimate and we will use data from both phases of the BA arm 
and only the phase 1 data from the AB arm in our estimates of outcomes and effect sizes. For 
VO2 max, we will assess for legitimate washout by 10 weeks after therapy by comparing T4 VO2 
for the AB patients to the T2 VO2 for the BA patients. If the values are within 20%, then we will 
perform paired within patient treatment comparisons and test H0 µ=0.  
 
All secondary outcomes are measured on a continuum. Effect size estimates will be based 
upon differences by phase, as well as differences by timepoint within each phase for each 
group. Statistical analyses will be performed on an intention-to-treat basis, with data analyzed 
according to the study arm to which the participant is assigned, regardless of adherence to the 
assigned intervention (oral LT3 treatment vs. placebo). If the two week washout period is 
legitimate, the treatment effect will be examined using paired t-tests and non-parametric 
Wilcoxon sign-rank tests, as appropriate, on the differences between the paired within-
participant outcome measures. However, if the washout period is in question, linear mixed-
effects model analyses74 will be conducted, where separate models will be generated for each 
of the outcome measures. Each outcome measure will be regressed on intervention group 
assignment (oral LT3 treatment vs. placebo), along with baseline outcome and any other 
covariates deemed prognostic in preliminary analyses. The fixed effect of interest will be the 
estimated effect reflecting the difference between intervention groups. Because each response 
variable represents a repeated measure, nested random effects will be modeled for the 
outcome of interest for each study participant and for each time period for each participant. The 
fit of the model will be examined by including a term for either study phase-by-intervention 

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
interaction or autocorrelation of the response variable over time, and compared statistically in 
terms of the estimated difference between study phases.75-77 The models will include participant-
specific intercepts as random effects, and will assume independent and identically distributed 
random errors within-participant. Restricted maximum likelihood estimation will be used, and an 
appropriate covariance matrix will be specified. Model assumptions will be examined (e.g., QQ 
plots to assess normally distributed residuals for valid Wald tests). All linear mixed-effects 
models will be analyzed using the SAS PROC MIXED procedure78 in SAS version 9.4 (SAS 
Institute, Inc., Cary, NC). A two-sided 0.05 level of significance will be used for both primary and 
secondary outcomes, without adjustment for multiple comparisons.  
7.3.1 Interim Analysis  
Since this is a safety study, there will be no interim efficacy analyses.  Non-inferential interim 
analyses will be performed regularly to ensure data collection and archiving procedures are 
operating correctly. Descriptive estimates of all measures will be generated for all patients at 
each observed follow-up time point, as well as by intervention group within each time point. 
Outliers will be visually inspected and checked for accuracy.  
7.4 
Participant Population(s) for Analysis 
The participant population for analysis will be the all-treated population. Any participants 
randomized into the study that received at least one dose of investigational product will be 
analyzed. A secondary analysis in the protocol-compliant population will be performed.  
8 
Safety and Adverse Events 
8.1 
Definitions 
8.1.1 Adverse Event 
 
An adverse event (AE) An adverse event (AE) is any untoward medical occurrence associated 
with the use of a drug in a subject whether or not considered drug or biologic related. An AE can 
therefore be any unfavorable and unintended sign, symptom or disease temporally associated 
with the use of the pharmaceutical product. 
 
8.1.2 Suspected Adverse Reaction 
 
A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the drug caused the event.  “Reasonable possibility” suggests there is a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug.     
8.1.3 Serious Adverse Event 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  An adverse event or suspected adverse 
reaction is considered serious if the investigator or sponsor believes any of the following outcomes 
may occur:  
 
A serious adverse event is any AE that is:  

Developing Oral T3 for Heart Failure 
 
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05/11/2022 
 fatal 
 life-threatening: place the participant at immediate risk of death at the time of the event as 
it occurred 
 persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions  
 requires inpatient hospitalization or prolongs hospital stay 
 a congenital anomaly or birth defect 
 important medical events may not result in death, be life threatening, or require 
hospitalization, but based on appropriate medical judgement, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition 
 
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance.  They may jeopardize the participant, and may require intervention 
to prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. This determination is based on the opinion of either the investigators, 
and/or DSMB (e.g.if any believe it is serious, it must be considered serious).   
8.1.4 Unanticipated Problems(UP) Involving Risk to Participants or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
 Suggests that the research places participants or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
8.1.5 Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
8.1.6 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  
At the end of the study, any new clinically significant findings/abnormalities that meet the definition 
of an adverse event must also be recorded and documented as an adverse event.  
8.1.7 Post-study Adverse Event 
All unresolved adverse events considered probably or definitely related should be followed by the 
investigator until the events are resolved, the participant is lost to follow-up, or the adverse event 
is otherwise explained.  At the last scheduled visit, the investigator should instruct each participant 
to report any subsequent event(s) that the participant, or the participant’s personal physician, 
believes might reasonably be related to participation in this study.   

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8.1.8 Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for additional surgery should be documented as an 
adverse event if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study 
(Heart Failure) unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
 
8.2 
Recording of Adverse Events 
At each contact with the participant, the investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events will 
be recorded immediately in the source document, and also in the appropriate adverse event 
module of the case report form (CRF) and entered into the study database. All clearly related 
signs, symptoms, and abnormal diagnostic procedures results should be recorded in the source 
document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period (through week 19) will be recorded.  The 
clinical course of each event will be followed until resolution, stabilization, or until it has been 
determined that the study intervention or participation is not the cause.  Serious adverse events 
that are still ongoing at the end of the study period will be followed up to determine the final 
outcome.  Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study intervention or study participation will be recorded and reported 
immediately. 
8.3 
Classification of Adverse Events 
Severity 
Study investigators (PI or Co-I) will use the below scale as a guide for determining the severity, 
causal relationship to study drug or research procedures, and “expectedness” of an adverse 
event.  
 
Classification of Adverse Events Regarding Severity Scale 
Grade 1 
Mild AE. Awareness of sign, symptom, or event, but easily tolerated; 
no treatment required 
Grade 2  
Moderate AE. Discomfort enough to cause interference with usual 
activity and may warrant intervention. In the latter scenario, AE 
responds to treatment. 

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Grade 3 
Severe AE. Incapacitating, limiting usual/normal activities or 
significantly affects clinical status requiring hospitalization or 
prolongation of hospitalization.  
Grade 4 
Life-threatening or disabling 
Grade 5 
Fatal AE 
 
Relatedness  
The relationship of each adverse event to the study procedures or to the study drug will be 
characterized and determined by the study PI or Co-I to and will be classified (related, possibly 
related, unlikely or unrelated).  The AE’s will be presented to the DSMB – see DSMP. 
 
 
 
Classification of Adverse Events for Causal Relationship to Study Drug 
Not related 
There is not a reasonable causal relationship to the drug and the adverse 
event. 
Unlikely related 
 
No temporal association or the cause of the event has been identified, or 
the drug or biologic cannot be implicated. 
Possibly related  
There is reasonable evidence to suggest a causal relationship between 
the drug and adverse event. 
 
Related 
 
 There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely  
 
 
 
 
Expectedness 
The expectedness of an AE or SAR shall be determined according to the participants’ underlying 
conditions, including all cardiac and non-cardiac diagnoses. Given the wide range of comorbidities 
associated with HF, expectedness will be assessed on a case-by case basis by the PIs.   
 
An unexpected AE is any AE occurring in one or more participants participating in a research 
protocol, the nature, severity, or frequency of which is not consistent with either: 
1) the known or foreseeable risk of AEs associated with the procedures involved in the 
research; or 
 
2)  the expected natural progression of any underlying disease (including heart failure and 
the specific comorbidities present in the individual study participant), disorder, or condition 
of the participant(s) experiencing the AE and the participant’s predisposing risk factor 
profile for the AE. 
 

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The following AEs are anticipated, disease-related events in patients with HF: 
 
Unplanned hospitalization, ER visit or clinic visit for worsening HF 
Arrhythmias, particularly atrial fibrillation 
Sudden cardiac death 
Acute coronary syndrome 
Cerebrovascular event 
Venous thromboembolism 
Lightheadedness 
Worsening renal function 
 
The following are potential expected side effects of LT3: 
Anxiety 
Irritability 
Tremor 
Warmth 
Palpitations 
Frequent bowel movements 
Shortness of breath  
8.4 
Reporting of Adverse Events and Unanticipated Problems 
  
8.4.1 Adverse Event Reporting Period 
 
The PIs will continuously supervise all aspects of the trial and review the records of the study 
participants following each visit and at the end of their participation. The period during which 
adverse events must be reported is defined as the period from the initiation of any study 
procedures (consent) to the end of the study follow-up (Week ~19 phone contact).  Adverse 
events that do not require expedited reporting (see section 8.5 below) will be reported in summary 
to the IRB at continuing review.  The PIs will be responsible for ensuring that all adverse events 
are noted, followed and reported to the IRB, and DSMB, as appropriate.  
.  
8.4.2 Expedited Reporting of Adverse Events and Unanticipated Problems 
SAEs occurring from signed informed consent to final visit will be captured on the SAE CRF. AEs 
will be classified according to the guidelines/definitions specified above. Cumulative adverse 
events are participant to full IRB review at least yearly and DSMB review every 6 months.   
 
 
Any SAE must be reported by the site investigator or qualified designee within 1 working day of 
first becoming aware of the event.   The IRB should be notified as per institutional guidelines and 
the NHLBI will be notified per required guidelines (see table below). The DSMB and site IRB, as 
appropriate, may make an immediate determination about the necessity to modify the protocol, 
include additional information in the consent form, inform previous participants, temporarily hold 
enrollment of patients, or terminate the study. The study will proceed only if the DSMB and site 
IRB all agree on this course of action. The PIs will notify the NHLBI if any of the IRB actions 
described above occur.   
 
Reporting will be consistent with regulatory and sponsor requirements for the study. At a minimum 
those events that must be reported to the IRB are those that are: 

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 Probably or definitely related to study participation and unexpected (report within 10 
business days), or 
 Probably related, unexpected and event suggests research places subject at greater risk 
than was previously known or recognized (report within 10 business days).   
 Probably or Definitely related death to study participation and unexpected (report within 3 
calendar days).  
The report will be submitted on a reportable event form and the minimum necessary information 
to be provided at the time of the initial report includes: 
 
Study identifier 
 
Study Center 
 
Participant number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as 
serious 
 
Investigator assessment of the association 
between the event and study treatment 
 
 
  
Within the following 72 hours, the investigator will provide further information (if available and 
needed) on the serious adverse event or the unanticipated problem in the form of a reportable 
event form.  This should include any diagnostic information that will assist the understanding of 
the event.  Significant new information on ongoing serious adverse events should be provided 
promptly to the study sponsor. 
 
8.4.3 Follow-up report 
The investigators will record follow-up information according to the same process used for 
reporting the initial event as described above. If an SAE has not resolved at the time of the initial 
report and new information arises that changes the investigator’s assessment of the event, a 
follow-up report including all relevant new or reassessed information (e.g., concomitant 
medication, medical history) should be submitted to the IRB.  The investigators will follow all 
reportable events until resolution, stabilization or the event is otherwise explained.  
 
What Event is Reported 
To Whom is Event 
Reported 
When is Event Reported 
Fatal 
or 
life 
threatening 
unexpected, suspected serious 
adverse reactions or adverse 
events 
 
 
 
Local IRB 
Within 3 calendar days (if probably or definitely related & 
unexpected) – summarize at CR 
 
NHLBI, DSMB 
Within 7 calendar days/1 week  of initial receipt of 
information 
Non-fatal, 
non-life-threatening 
unexpected, suspected serious 
adverse reactions 
 
 
 
Local IRB 
Within 10 business days  of the investigator becoming 
aware of the problem (if probably or definitely related & 
unexpected) – summarize at CR 
 
NHLBI 
Within 15 calendar days of initial receipt of information 
Unanticipated Problem that is not 
an SAE (see above definition of 
UP) 
 
 
 
Local IRB 
Within 10 business days of the investigator becoming 
aware of the problem 
 
NHLBI 
Within 14 calendar days of the investigator becoming 
aware of the problem 
All Unanticipated Problems 
 
OHRP (reported by 
IRB) 
Within 30 days of the IRB’s receipt of the report 

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The DSMB will review detailed safety data approximately every 6 months throughout the study 
(or at a frequency determined by the DSMB).  
 
8.5 
Management of Adverse Events-Criteria for Study Drug Discontinuation 
Management of probably related or possibly related AEs may be managed with dose reduction 
or discontinuation of study drug. Study drug maybe discontinued in the event of an unexpected 
SAE. In this study population, heart failure is not an unexpected AE or SAE.   
8.6 
Unblinding Procedures 
Any intentional breaking of the blind prior to study completion, which may be necessary, for 
example, in the case of an SAE that requires knowledge of the treatment assignment for clinical 
care, or directive of the DSMB will be done in conjunction with the IDS, whose responsibility it will 
be to notify a designated member of the research team of the individual participant’s treatment 
assignment. Any intentional or unintentional breaking of the blind prior to study completion will be 
documented and reported to the IRB within 24 hours.  
8.7 
Stopping Rules  
There are no formal stopping rules for the study. However, the study will be stopped if the following 
criteria occur: 
1. The PI discovers a condition or conditions that indicate unacceptable risk to the participants. 
2. There is evidence of harm of study-related treatments or procedures to the participants. 
3. As directed by the DSMB or IRB for the study. 
8.8 
Oversight and Monitoring 
  
8.8.1 Data and Safety Monitoring Plan 
To ensure the protection of participants’ rights, the safety of participants enrolled in the trial, and 
the integrity and quality of the resulting data this study will be monitored as per the Data and 
Safety Monitoring Plan (DSMP) developed for this particular study. This DSMP describes the 
specifications for monitoring, which will be identical between the HFrEF and HFpEF studies. The 
study shall adhere to the requirements described in the protocol, the International Conference on 
Harmonization (ICH), FDA Good Clinical Practice (GCP), and SOPs. In addition to PI monitoring, 
there will be a DSMB. We will also implement an internal monitoring plan.  
 
Study Monitor: The PIs plan to mirror OCRs monitoring standards (and monitoring forms) in 
efforts to ensure the rigor of safety data collected. The Cardiology Clinical Research Unit (CCRU) 
has been enlisted to perform this function.  The PIs will provide a monitoring plan and associated 
documents (protocol, Informed Consent Form; ICF), Standard Operating Procedures (SOPs) to 
the Monitor. The Monitor is qualified by education, experience, and training of Good Clinical 
Practice requirements as well as regulatory compliance. Details for the internal study monitored 
are provided in the DSMP. 
 
 
Data and Safety Monitoring Board: (see section 8.8.2) 
 
8.8.2 Data Safety Monitoring Board  
An independent DSMB will be assembled. The DSMB will have four members, including at least 

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one cardiologist with expertise in heart failure, one cardiologist with expertise in clinical trials, one 
endocrinologist, and one biostatistician. Penn’s conflict of interest policy will be followed. No 
member of the DSMB will have direct involvement in the conduct of the study. Furthermore, no 
member will have financial, proprietary, professional, or other interests that may affect impartial, 
independent decision-making by the DSMB. All DSMB members will sign a Conflict of Interest 
certification to that effect at the time they are asked to participate. Interests that may create a 
potential conflict of interest should be disclosed to the DSMB prior to any further discussion. The 
DSMB will determine how to handle a potential conflict. The DSMB can require that a member 
with a potential conflict not vote or take other means deemed appropriate.  
 
The primary responsibilities of the DSMB will be to 1) periodically review and evaluate the 
accumulated study data for participant safety, study conduct and progress, and 2) make 
determinations concerning the continuation, modification, or termination of the trials. The DSMB 
will review the study protocol prior to implementation of the study and may request changes to 
adverse event monitoring procedures. 
 
 
Interim Analyses and Stopping Rules:  Since the proposed study is a safety study, there will be 
no interim efficacy analyses. Safety will be assessed in real time. We have not proposed stopping 
rules, and we will allow the DSMB to assess safety without predetermined stopping rules. 
9 
Study Administration, Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed participant authorization informing the participant of the following:  
 What protected health information (PHI) will be collected from participants in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research participant to revoke their authorization for use of their PHI.  
 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is alive) 
at the end of their scheduled study period. 
9.2 
Data Collection and Management  
Data for the proposed trial will be collected by the research staff during each study visit using trial-
specific and visit-specific data collection forms. All source documents collected in this trial will be 
housed inside of a locked cabinet in on the 12th floor of the Smilow Center for Translational 
Research.  
Data capture and storage will be accomplished using electronic case report forms (eCRFs) within 
the framework of the Research Electronic Data Capture (REDCap) project. REDCap is a secure, 
web-based application designed exclusively to support data capture for research studies. It 
provides an intuitive interface for data entry with data validation, audit trails for tracking data 
manipulation and export procedures, automated export procedures for seamless data downloads 
to common statistical packages and procedures for importing data from external sources. As part 
of our standard practice, a series of computerized data validation checks will also be programmed 

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into the REDCap eCRF system to check for missing data, inconsistencies in the data, or data that 
is out of range. 
Once the REDCap database is launched into production mode, study coordinators will be 
responsible for transmitting participant coded electronic data using eCRFs, which will be 
subjected to quality checks for accuracy and completeness.  
9.3 
Records Retention  
Study records, including administrative and participant related source and CRFs, will be retained 
for 7 years after the completion of the research (often marked by a final progress report).  
   
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
The investigator and research team will allocate adequate time for such monitoring activities (as 
described in section 8.8 or by additional regulatory entities.  The Investigator will also ensure that 
the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. CHPS unit), and has adequate 
space to conduct the monitoring visit.   
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
11 Ethical Considerations 
 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Penn Institutional Review Board (IRB), 
for formal approval of the study conduct.   
 
All participants for this study will be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation in this 
study.  See Attachment 1 for a copy of the Participant Informed Consent Form.  This consent form 
will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a participant, using the IRB-approved consent form, must be obtained before that 
participant undergoes any study procedure.  The consent form must be signed by the participant 
or legally acceptable surrogate, and the investigator-designated research professional obtaining 
the consent.  

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11.1 Risks 
LT3: LT3 has been in therapeutic use for more than 60 years. Adverse reactions to LT3 are 
exclusively related to excessive thyroid hormone, which can produce symptoms of thyrotoxicosis 
and increased risk of atrial tachyarrhythmias. We will be frequently monitoring the thyroid function 
via blood test during LT3 treatment.  Adverse reactions will be averted by a low initial dose of LT3 
and gradual dose titration. There will be monitoring for AE’s during weekly calls and each patient 
will have a phone number to call 24 hours for assistance.    
 
Cardiopulmonary stress test: This test is used extensively for research purposes with minimal 
risk to participants. The most significant risks of the test are dysrhythmias or other cardiovascular 
complications, which are extremely rare. These procedures will be performed by qualified 
personnel according to established American Heart Association guidelines,79,80 Non-
revascularized myocardial ischemia, which may increase the risk of complications during exercise 
testing, is an exclusion criterion for the study. 
 
Participants may feel uncomfortable as a result of pushing themselves during the maximal effort 
exercise test. Participants will likely feel short of breath and fatigued as a result of the exercise 
test. Various other complaints, such as nausea, lightheadedness, and other aches and pains are 
also possible as a result of the maximal effort exercise study. Although exercise testing may result 
in exhaustion, rarely do people develop abnormal heart rate or heart complications during 
exercise tests. The risk of this happening is the same as if the participant would exert themselves 
during stressful situations or during exercise elsewhere. 
 
We will perform EKG, heart rate, and blood pressure monitoring during our exercise test. In 
addition to the blood pressure (generally increases) and heart rate (generally increases) changes 
during exercise, we will also monitor arterial saturation. This will be done non-invasively using a 
pulse oximeter. Of note, oxygen levels can decrease with exercise, even in individuals without 
significant cardiopulmonary disease.81,82 If the arterial saturation falls to below 88% (“severe 
exercise induced hypoxemia”82), we will alert the care provider as this may prompt consideration 
for additional/alternative causes for arterial hypoxemia. 
 
Arterial tonometry, echocardiogram, resting energy expenditure, actigraphy: These are 
non-invasive procedures and do not have any known significant risks. It is possible that 
participants may experience mild, temporary discomfort or skin irritation from the tonometry 
sensor, echo probe, or from wearing the actigraph. 
 
Phlebotomy: The risk of phlebotomy is low. All phlebotomy will be performed by study personnel 
who are trained and experienced in drawing blood. Risks include minor discomfort, minor bruising, 
bleeding, hematoma and/or fainting associated with the drawing of blood. There is also a very 
small chance (less than 1%) of infection at the blood draw site. The amount of blood drawn will 
be 10 cc/visit. 
 
Cardiac Monitoring Device: Shaving the area where adhesive electrodes will be attached as 
well as attachment of adhesive electrodes to the participant’s skin may cause skin itching and 
irritation. 
 
Questionnaire (KCCQ, ThyPRO) completion: Participants may become uncomfortable with 
questions or feel sadness as a result of completing questionnaires.  
 

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Confidentiality: There is a potential for a breach of confidentiality. The individual research record 
kept on each participant will be kept in a locked cabinet exclusively available to PI and study team.  
Confidentiality will be maintained by assigning an identification code to each participant, entering 
and retrieving data in computers by code, and keeping codes in a locked file accessible only by 
investigators.  Ongoing commitment to stringently protecting confidentiality will be maintained.  
 
11.2 Benefits 
The proposed research is not expected to benefit research participants. It is possible that 
participants may experience improvement in symptoms of hypothyroidism or heart failure while 
taking LT3. The major risk is administration of too high a dose of LT3.  Potential participants may 
choose to participate or not to participate.   
11.3 Risk Benefit Assessment 
New therapies are needed for HFrEF and HFpEF. The risks are reasonable in relation to the 
importance of the knowledge to be acquired. The proposed studies are essential to determine the 
therapeutic potential of LT3 in patients with HFrEF.  
 
11.4 Informed Consent Process / HIPAA Authorization  
All participants will be provided a consent form describing the study. Obtaining informed consent 
will be a process whereby information and explanation is provided to each potential participant 
regarding the research study events and procedures in a private or semi-private location.  
Sufficient time will be allotted to hear and respond to all potential participant questions and 
concerns to provide informed decisions about participation in this study. The formal consent of a 
participant, using the IRB-approved consent form, will be obtained before that participant 
undergoes any study procedure.  The consent form will be signed by the participant and the 
investigator-designated research professional obtaining the consent.  The process of consent 
will be documented.   
 
12 Study Finances 
12.1 Funding Source 
This study is financed through a grant from the United States National Heart, Lung, and Blood 
Institute, National Institutes of Health 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All University of Pennsylvania investigators will follow the University 
conflict of interest policy. 
 
12.3 Participant Stipends or Payments 
Participants will receive $400 for completing the study as payment for time, effort, and 
inconvenience of being in the study. In addition, they will be provided parking vouchers to park at 
Penn Presbyterian Hospital.  

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13 Publication Plan 
 
Study results will be published in peer-reviewed publication. The final, peer-reviewed journal 
manuscript will be submitted to PubMed Central as per NIH guidelines.  
 
The trial(s) will be registered in www.ClinicalTrials.gov prior to initiation. Registrations will be 
updated to reflect any protocol amendments during the course of the study. Trial results will be 
uploaded at the time of publication or within one year of trial completion, whichever comes first. 
Informed consent documents will include a specific statement relating to posting of clinical trial 
information at ClinicalTrials.gov. The University of Pennsylvania has an internal policy in place 
to ensure that clinical trials registration and results reporting occur in compliance with policy 
requirements.  
 
14 References 
1. 
Braunwald E. Heart failure. JACC Heart Fail. 2013;1(1):1-20. 
2. 
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 
update: a report from the American Heart Association. Circulation. 2015;131(4):e29-322. 
3. 
Chirinos JA. Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 1): 
Physiologic and Technical Considerations. J Cardiovasc Transl Res. 2017;10(3):245-259. 
4. 
Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S. Thyroid hormones and 
cardiovascular disease. Nat Rev Cardiol. 2017;14(1):39-55. 
5. 
Ascheim DD, Hryniewicz K. Thyroid hormone metabolism in patients with congestive heart 
failure: the low triiodothyronine state. Thyroid. 2002;12(6):511-515. 
6. 
Passino C, Pingitore A, Landi P, et al. Prognostic value of combined measurement of brain 
natriuretic peptide and triiodothyronine in heart failure. J Card Fail. 2009;15(1):35-40. 
7. 
Wang W, Guan H, Fang W, et al. Free Triiodothyronine Level Correlates with Myocardial 
Injury and Prognosis in Idiopathic Dilated Cardiomyopathy: Evidence from Cardiac MRI 
and SPECT/PET Imaging. Sci Rep. 2016;6:39811. 
8. 
Iervasi G, Pingitore A, Landi P, et al. Low-T3 syndrome: a strong prognostic predictor of 
death in patients with heart disease. Circulation. 2003;107(5):708-713. 
9. 
Pingitore A, Landi P, Taddei MC, Ripoli A, L'Abbate A, Iervasi G. Triiodothyronine levels 
for risk stratification of patients with chronic heart failure. Am J Med. 2005;118(2):132-136. 
10. 
Kannan L, Shaw PA, Morley MP, et al. Thyroid Dysfunction in Heart Failure and 
Cardiovascular Outcomes. Circ Heart Fail. 2018;11(12):e005266. 
11. 
Selvaraj S, Klein I, Danzi S, Akhter N, Bonow RO, Shah SJ. Association of serum 
triiodothyronine with B-type natriuretic peptide and severe left ventricular diastolic 
dysfunction in heart failure with preserved ejection fraction. Am J Cardiol. 
2012;110(2):234-239. 
12. 
Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine 
in blacks with heart failure. N Engl J Med. 2004;351(20):2049-2057. 
13. 
Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure 
(SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885. 
14. 
O'Connor CM, Gattis WA, Uretsky BF, et al. Continuous intravenous dobutamine is 
associated with an increased risk of death in patients with advanced heart failure: insights 
from the Flolan International Randomized Survival Trial (FIRST). American heart journal. 
1999;138(1 Pt 1):78-86. 
15. 
Cuffe MS, Califf RM, Adams KF, Jr., et al. Short-term intravenous milrinone for acute 
exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 
2002;287(12):1541-1547. 

Developing Oral T3 for Heart Failure 
 
Page 38 
 
 
05/11/2022 
16. 
Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with 
vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators [see 
comments]. NEnglJMed. 1998;339(25):1810-1816. 
17. 
Adams KF, Jr., Patterson JH, Gattis WA, et al. Relationship of serum digoxin concentration 
to mortality and morbidity in women in the digitalis investigation group trial: a retrospective 
analysis. J Am Coll Cardiol. 2005;46(3):497-504. 
18. 
Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin 
concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871-878. 
19. 
Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of 
heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13(1):18-28. 
20. 
Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 
in heart failure with preserved ejection fraction: a phase 2 double-blind randomised 
controlled trial. Lancet. 2012;380(9851):1387-1395. 
21. 
Zamani P, Rawat D, Shiva-Kumar P, et al. Effect of inorganic nitrate on exercise capacity 
in heart failure with preserved ejection fraction. Circulation. 2015;131(4):371-380; 
discussion 380. 
22. 
Chirinos JA, Zamani P. The Nitrate-Nitrite-NO Pathway and Its Implications for Heart 
Failure and Preserved Ejection Fraction. Curr Heart Fail Rep. 2016;13(1):47-59. 
23. 
Zamani P, Tan V, Soto-Calderon H, et al. Pharmacokinetics and Pharmacodynamics of 
Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction. Circ Res. 
2017;120(7):1151-1161. 
24. 
Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics 
and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll 
Cardiol. 2015;66(15):1672-1682. 
25. 
Eggebeen J, Kim-Shapiro DB, Haykowsky M, et al. One Week of Daily Dosing With 
Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients 
With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016;4(6):428-437. 
26. 
Voors AA, Gori M, Liu LC, et al. Renal effects of the angiotensin receptor neprilysin 
inhibitor LCZ696 in patients with heart failure and preserved ejection fraction. Eur J Heart 
Fail. 2015;17(5):510-517. 
27. 
Zile MR, Jhund PS, Baicu CF, et al. Plasma Biomarkers Reflecting Profibrotic Processes 
in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective 
Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection 
Fraction Study. Circ Heart Fail. 2016;9(1). 
28. 
Jhund PS, Claggett B, Packer M, et al. Independence of the blood pressure lowering effect 
and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart 
failure with preserved ejection fraction: an analysis of the PARAMOUNT trial. Eur J Heart 
Fail. 2014;16(6):671-677. 
29. 
Chirinos JA. Deep Phenotyping of Systemic Arterial Hemodynamics in HFpEF (Part 2): 
Clinical and Therapeutic Considerations. J Cardiovasc Transl Res. 2017;10(3):261-274. 
30. 
Leggio GM, Incognito T, Privitera G, Marano MR, Drago F. Comparative bioavailability of 
different formulations of levothyroxine and liothyronine in healthy volunteers. J Endocrinol 
Invest. 2006;29(11):RC35-38. 
31. 
Davis PJ, Goglia F, Leonard JL. Nongenomic actions of thyroid hormone. Nat Rev 
Endocrinol. 2016;12(2):111-121. 
32. 
Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, Morreale de Escobar G. 
Replacement therapy for hypothyroidism with thyroxine alone does not ensure 
euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Invest. 
1995;96(6):2828-2838. 

Developing Oral T3 for Heart Failure 
 
Page 39 
 
 
05/11/2022 
33. 
Liu Y, Redetzke RA, Said S, Pottala JV, de Escobar GM, Gerdes AM. Serum thyroid 
hormone levels may not accurately reflect thyroid tissue levels and cardiac function in mild 
hypothyroidism. Am J Physiol Heart Circ Physiol. 2008;294(5):H2137-2143. 
34. 
Henderson KK, Danzi S, Paul JT, Leya G, Klein I, Samarel AM. Physiological replacement 
of T3 improves left ventricular function in an animal model of myocardial infarction-induced 
congestive heart failure. Circ Heart Fail. 2009;2(3):243-252. 
35. 
Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 
2010;122(4):385-393. 
36. 
Murray GR. Note on the Treatment of Myxoedema by Hypodermic Injections of an Extract 
of the Thyroid Gland of a Sheep. Br Med J. 1891;2(1606):796-797. 
37. 
Harington CR. Chemistry of Thyroxine: Constitution and Synthesis of Desiodo-Thyroxine. 
Biochem J. 1926;20(2):300-313. 
38. 
McGavack TH, Reckendorf HK. Therapeutic activity of desiccated thyroid substance, 
sodium L-thyroxine and D, L-triiodothyronine; a comparative study. Am J Med. 
1956;20(5):774-777. 
39. 
Braverman LE, Ingbar SH, Sterling K. Conversion of thyroxine (T4) to triiodothyronine (T3) 
in athyreotic human subjects. J Clin Invest. 1970;49(5):855-864. 
40. 
Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: 
prepared by the american thyroid association task force on thyroid hormone replacement. 
Thyroid. 2014;24(12):1670-1751. 
41. 
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA Guidelines: 
The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur Thyroid J. 2012;1(2):55-
71. 
42. 
Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor 
for atrial fibrillation in older persons. N Engl J Med. 1994;331(19):1249-1252. 
43. 
Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality 
in older adults. JAMA. 2006;295(9):1033-1041. 
44. 
Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of 
coronary heart disease and mortality. Arch Intern Med. 2012;172(10):799-809. 
45. 
Jackson IM, Cobb WE. Why does anyone still use desiccated thyroid USP? Am J Med. 
1978;64(2):284-288. 
46. 
Celi FS, Zemskova M, Linderman JD, et al. Metabolic effects of liothyronine therapy in 
hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus 
levothyroxine. J Clin Endocrinol Metab. 2011;96(11):3466-3474. 
47. 
Leese GP, Soto-Pedre E, Donnelly LA. Liothyronine use in a 17 year observational 
population-based study - the tears study. Clin Endocrinol (Oxf). 2016;85(6):918-925. 
48. 
Bennett-Guerrero E, Jimenez JL, White WD, D'Amico EB, Baldwin BI, Schwinn DA. 
Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary 
artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke 
T3 study group. JAMA. 1996;275(9):687-692. 
49. 
Malik FS, Mehra MR, Uber PA, Park MH, Scott RL, Van Meter CH. Intravenous thyroid 
hormone supplementation in heart failure with cardiogenic shock. J Card Fail. 
1999;5(1):31-37. 
50. 
Hamilton MA, Stevenson LW, Fonarow GC, et al. Safety and hemodynamic effects of 
intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol. 
1998;81(4):443-447. 
51. 
Pingitore A, Galli E, Barison A, et al. Acute effects of triiodothyronine (T3) replacement 
therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, 
placebo-controlled study. J Clin Endocrinol Metab. 2008;93(4):1351-1358. 

Developing Oral T3 for Heart Failure 
 
Page 40 
 
 
05/11/2022 
52. 
Holmager P, Schmidt U, Mark P, et al. Long-term L-Triiodothyronine (T3) treatment in 
stable systolic heart failure patients: a randomised, double-blind, cross-over, placebo-
controlled intervention study. Clin Endocrinol (Oxf). 2015;83(6):931-937. 
53. 
Goldman S, McCarren M, Morkin E, et al. DITPA (3,5-Diiodothyropropionic Acid), a thyroid 
hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. 
Circulation. 2009;119(24):3093-3100. 
54. 
Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM. Twenty-four hour 
hormone profiles of TSH, Free T3 and free T4 in hypothyroid patients on combined T3/T4 
therapy. Exp Clin Endocrinol Diabetes. 2007;115(4):261-267. 
55. 
Celi FS, Zemskova M, Linderman JD, et al. The pharmacodynamic equivalence of 
levothyroxine and liothyronine: a randomized, double blind, cross-over study in 
thyroidectomized patients. Clin Endocrinol (Oxf). 2010;72(5):709-715. 
56. 
Russell W, Harrison RF, Smith N, et al. Free triiodothyronine has a distinct circadian 
rhythm that is delayed but parallels thyrotropin levels. J Clin Endocrinol Metab. 
2008;93(6):2300-2306. 
57. 
Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum 
T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. 
J Clin Endocrinol Metab. 2002;87(3):1068-1072. 
58. 
https://www.thyroid.org/thyroid-function-tests/. Accessed 10/8/17. 
59. 
Nichols WW ORM, Vlachopoulos C. McDonald’s blood flow in arteries. Theoretical, 
Experimental and Clinical Principles. . 6 ed: Hodder Arnold; 2011. 
60. 
Coleman A, Freeman P, Steel S, Shennan A. Validation of the Omron 705IT (HEM-759-
E) oscillometric blood pressure monitoring device according to the British Hypertension 
Society protocol. Blood Press Monit. 2006;11(1):27-32. 
61. 
Segers P, Rietzschel ER, De Buyzere ML, et al. Noninvasive (input) impedance, pulse 
wave velocity, and wave reflection in healthy middle-aged men and women. Hypertension. 
2007;49(6):1248-1255. 
62. 
Batterham A, Shave R, Oxborough D, Whyte G, George K. Longitudinal plane colour 
tissue-Doppler myocardial velocities and their association with left ventricular length, 
volume, and mass in humans. Eur J Echocardiogr. 2008;9(4):542-546. 
63. 
Arts T, Bovendeerd PH, Prinzen FW, Reneman RS. Relation between left ventricular 
cavity pressure and volume and systolic fiber stress and strain in the wall. Biophys J. 
1991;59(1):93-102. 
64. 
Chirinos JA, Segers P, Gupta AK, et al. Time-varying myocardial stress and systolic 
pressure-stress relationship: role in myocardial-arterial coupling in hypertension. 
Circulation. 2009;119(21):2798-2807. 
65. 
Chirinos JA, Segers P, Rietzschel ER, et al. Early and late systolic wall stress differentially 
relate to myocardial contraction and relaxation in middle-aged adults: the Asklepios study. 
Hypertension. 2013;61(2):296-303. 
66. 
Chirinos JA, Segers P, Gillebert TC, et al. Arterial properties as determinants of time-
varying myocardial stress in humans. Hypertension. 2012;60(1):64-70. 
67. 
Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 1: pressure 
and flow measurements and basic principles of wave conduction and reflection. 
Hypertension. 2010;56(4):555-562. 
68. 
Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 2: arterial 
pressure-flow and pressure-volume relations in humans. Hypertension. 2010;56(4):563-
570. 
69. 
Westerhof N, Sipkema P, van den Bos GC, Elzinga G. Forward and backward waves in 
the arterial system. Cardiovasc Res. 1972;6(6):648-656. 

Developing Oral T3 for Heart Failure 
 
Page 41 
 
 
05/11/2022 
70. 
Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the 
Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. 
Journal of the American College of Cardiology. 2000;35(5):1245-1255. 
71. 
Watt T, Bjorner JB, Groenvold M, et al. Establishing construct validity for the thyroid-
specific patient reported outcome measure (ThyPRO): an initial examination. Qual Life 
Res. 2009;18(4):483-496. 
72. 
Watt T, Cramon P, Hegedus L, et al. The thyroid-related quality of life measure ThyPRO 
has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol 
Metab. 2014;99(10):3708-3717. 
73. 
Watt T, Hegedus L, Groenvold M, et al. Validity and reliability of the novel thyroid-specific 
quality of life questionnaire, ThyPRO. Eur J Endocrinol. 2010;162(1):161-167. 
74. 
Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 
1982;38(4):963-974. 
75. 
Willan AR, Pater JL. Carryover and the two-period crossover clinical trial. Biometrics. 
1986;42(3):593-599. 
76. 
Grizzle JE. The Two-Period Change-over Design an Its Use in Clinical Trials. Biometrics. 
1965;21:467-480. 
77. 
Brown BW, Jr. The crossover experiment for clinical trials. Biometrics. 1980;36(1):69-79. 
78. 
Singer J. Using SAS PROC MIXED to Fit Multilevel Models, Hierarchical Models, and 
Individual Growth Models. J Educ Behav Stat.24:323-355. 
79. 
Balady GJ, Arena R, Sietsema K, et al. Clinician's Guide to cardiopulmonary exercise 
testing in adults: a scientific statement from the American Heart Association. Circulation. 
2010;122(2):191-225. 
80. 
Myers J, Forman DE, Balady GJ, et al. Supervision of exercise testing by nonphysicians: 
a 
scientific 
statement 
from 
the 
American 
Heart 
Association. 
Circulation. 
2014;130(12):1014-1027. 
81. 
Hadeli KO, Siegel EM, Sherrill DL, Beck KC, Enright PL. Predictors of oxygen desaturation 
during submaximal exercise in 8,000 patients. Chest. 2001;120(1):88-92. 
82. 
Dempsey JA, Wagner PD. Exercise-induced arterial hypoxemia. J Appl Physiol (1985). 
1999;87(6):1997-2006. 
 
15 Attachments 
16 Appendix 
Thyroid hormone preparation: 
1.Liothyronine 
 
Antithyroid medication: 
1. methimazole 
2. propylthiouracil 
 
Medication that interferes with LT3 absorption or metabolism or thyroid function test interpretation: 
1. lithium 
2. amiodarone 
3. cholestyramine 
4. colestipol 
5. colesevelam 
6. interferon 
7. ipilimumab 
8.  alemtuzumab 

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9.  pembrolizumab 
10.  sunitinib 
11.  sorafenib 
12.  bexarotene 
13.  phenytoin 
14.  carbamazepine 
15.  rifampin 
16.  phenobarbital 
17.  octreotide, somatostatin 
 
16.1 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, participants’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, participant files, and records kept 
at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial. 
16.2 Case Report Forms (CRFs) 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the 
CRF is left blank because the procedure was not done or the question was not asked, write “N/D”.  
If the item is not applicable to the individual case, write “N/A”.  All entries should be printed legibly 
in black ink.  If any entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes must be initialed 
and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it.