Triiodothyronine (T3) for Heart Failure

Not currently recruiting at 1 trial location

Overseen By Arshed A. Quyyumi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Emory University

Must be taking: Metoprolol succinate

Disqualifiers: Atrial fibrillation, Non-ischemic HF, Liver dysfunction, Endocrine disorders, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 14

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the thyroid hormone triiodothyronine (T3) can safely improve heart failure symptoms. Researchers will divide participants into groups, with some receiving T3 and others not, to compare effects. Those not initially receiving the drug may have a chance to try it later in the study. This trial suits individuals with stable heart failure who have managed their condition with standard treatments for over a month and have a specific heart condition (left ventricular ejection fraction ≤ 40%). As a Phase 1, Phase 2 trial, this research aims to understand how T3 works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking heart failure treatment research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that patients on other beta-blockers will be switched to metoprolol succinate for 3 weeks. It's best to discuss your specific medications with the study team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that triiodothyronine (T3), a thyroid hormone, can be safe for people with heart failure when administered carefully. One study found that heart failure patients with low T3 levels took T3 orally without major safety issues, although their heart rates increased. Another study determined that T3 did not cause serious health problems or death when closely monitored. However, a study from Korea noted some risks, indicating an increased chance of heart failure and strokes in long-term T3 users with a history of thyroid cancer. This suggests that while T3 can be safe, it might not suit everyone, especially in certain long-term or high-risk situations.

Overall, T3 appears well-tolerated when used correctly and monitored, but risks exist in certain conditions. This indicates it might be a promising treatment for heart failure, but individual health conditions must be considered carefully. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for heart failure?

Researchers are excited about Triiodothyronine (T3) for heart failure because it offers a unique approach compared to current treatments like ACE inhibitors, beta-blockers, and diuretics. Unlike these standard options that primarily work by managing symptoms and reducing strain on the heart, T3 directly targets thyroid hormone levels, which can influence heart function and metabolism. This approach could potentially improve heart muscle performance and energy use more directly, offering a new avenue for managing heart failure. Additionally, T3 administration in this trial is designed to show effects in just a few days, which could mean faster relief for patients.

What evidence suggests that triiodothyronine (T3) might be an effective treatment for heart failure?

Research has shown that a thyroid hormone called triiodothyronine (T3) can aid people with heart failure. Studies have found that T3 therapy improves heart function in those with low levels of this hormone, a common condition in heart failure. In this trial, participants will receive T3 treatment in different phases. Some will receive ascending doses, while others will receive a stable dose. Previous studies have demonstrated that T3 treatment increases T3 levels in the body without causing major side effects. Overall, evidence suggests that T3 could enhance heart function in heart failure patients. ^{1 2 6 7 8}

Who Is on the Research Team?

Arshed A. Quyyumi, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with ischemic heart failure and a left ventricular ejection fraction (LVEF) ≤ 40%. They must be stable, on standard heart failure therapies including metoprolol succinate, and have an ICD or CRT-D device. Excluded are those with recent cardiac events, other drug trials within 3 months, endocrine disorders like thyroid disease, severe blood pressure issues, liver or kidney dysfunction, severe neurological disorders, life-limiting cancer history or planning major surgery.

Inclusion Criteria

Presence of ICD for >1 month or implantable cardiac resynchronization therapy defibrillator (CRT-D) for >3 months

My heart's pumping ability is reduced (LVEF ≤ 40%).

My heart condition is stable and I haven't been hospitalized for it recently.

Exclusion Criteria

Those who have participated in any drug clinical trial within the previous 3 months

I have ongoing atrial fibrillation or serious ventricular tachycardia.

LVEF > 40%

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase IA Treatment

Participants receive ascending doses of T3 (5 µg orally twice daily for the first 2 days and 10 µg orally twice daily for the next 3 days) with monitoring

5 days

5 visits (in-person at GCRC)

Phase IB Treatment

Participants receive adjusted doses of T3 (10 µg orally twice daily on day 1 and 20 µg twice daily from day 2 to 5) based on safety data

5 days

5 visits (in-person at GCRC)

Phase II Treatment

Participants receive a stable dose of T3 (20 µg orally twice daily for 5 days) after completing Phase I

5 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

4 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Triiodothyronine (T3)

Trial Overview The study tests if Triiodothyronine (T3), a thyroid hormone can safely improve symptoms of ischemic heart failure. Participants have equal chances to receive T3 or no treatment initially; non-treated in Phase 1 may get T3 in Phase 2. The first group stays at the GCRC for monitoring over five days plus follow-ups; the second has outpatient visits.

How Is the Trial Designed?

Group I: Experimental Phase II Experimental Treatment 1 Intervention

Patients who were enrolled in the open-label control group of Phase I and who have completed the 3-month follow-up will be permitted to enroll in Phase II. This Phase will start treatment after completion of Phase I and approval from the Data and Safety Monitoring Board (DSMB) to proceed with a single cohort that will receive a stable dose of the study drug (20 µg T3 orally twice daily for 5 days).

Group II: Experimental Phase IB Experimental Treatment 1 Intervention

In Phase IB, dose adjustments will be calculated while accounting for laboratory and safety data from the first two participants (Phase IA) for the remaining 3 participants within the treatment arm of Phase I. Participants 3 to 5 will receive 10 µg T3 orally twice daily on day 1 and 20 µg T3 twice daily from day 2 to 5.

Group III: Experimental Phase IA Experimental Treatment 1 Intervention

In Phase IA two participants (1 and 2) will receive ascending dose levels of the study drug (5 µg T3 orally twice daily for the first 2 days and 10 µg T3 orally twice daily for the next 3 days).

Group IV: Control Group-Phase IA and IB Placebo Group 1 Intervention

The control group will have testing as the experimental group but will not be given any medications.

Triiodothyronine (T3) is already approved in European Union, United States for the following indications:

Approved in European Union as Liothyronine for:

• Hypothyroidism
• Heart failure with low-T3 syndrome

Approved in United States as Liothyronine for:

• Hypothyroidism
• Heart failure with low-T3 syndrome

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Published Research Related to This Trial

In a study of 133 heart failure patients, low plasma levels of triiodothyronine (T3) were linked to more severe heart failure symptoms, including older age, lower functional capacity, and higher levels of NT-proBNP, a marker of heart stress.

The lowest T3 levels were also associated with unfavorable hormonal and metabolic changes, such as lower DHEAS levels and worse renal function, suggesting that T3 may play a critical role in the overall health of heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low plasma triiodothyronine levels in heart failure are associated with a reduced anabolic state and membrane damage. Brenta, G., Thierer, J., Sutton, M., et al.[2016]

In a pilot study involving 52 patients with anterior myocardial infarction, acute treatment with liothyronine (LT3) showed a significant reduction in left ventricular end-diastolic and systolic volumes at hospital discharge, suggesting improved cardiac function immediately after treatment.

While LT3 treatment did not significantly improve left ventricular ejection fraction at 6 months compared to placebo, there was a trend towards lower infarct volume in the LT3 group, alongside a potential increased risk of atrial fibrillation shortly after treatment, indicating the need for further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Acute Triiodothyronine Treatment in Patients with Anterior Myocardial Infarction Undergoing Primary Angioplasty: Evidence from a Pilot Randomized Clinical Trial (ThyRepair Study). Pantos, CI., Trikas, AG., Pissimisis, EG., et al.[2022]

In a study of 60 patients with severe acute decompensated heart failure, 23% exhibited low-triiodothyronine syndrome (LT3S), and treatment with dobutamine significantly improved cardiac function and increased free T3 levels, indicating a potential for reversibility of LT3S.

The dobutamine infusion led to notable hemodynamic improvements, including increased cardiac index and decreased pulmonary capillary wedge pressure, suggesting that LT3S may serve as a useful marker for assessing the clinical status and progression of heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of short-term infusive dobutamine therapy on thyroid hormone profile and hemodynamic parameters in patients with acute worsening heart failure and low-triiodothyronine syndrome. D'Aloia, A., Vizzardi, E., Bugatti, S., et al.[2016]

In patients with advanced heart failure, low levels of triiodothyronine (T3) and a low T3/reverse T3 ratio were strongly linked to higher mortality, suggesting that thyroid hormone levels are critical for survival in this condition.

A preliminary safety study of intravenous T3 administration in 23 heart failure patients showed no adverse effects and some patients experienced increased cardiac output, indicating potential benefits of T3 therapy in managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroid hormone abnormalities in heart failure: possibilities for therapy. Hamilton, MA., Stevenson, LW.[2022]

A study involving 1434 patients using liothyronine (LT3) and 3908 patients using levothyroxine (LT4) found that LT3 users had a significantly higher risk of heart failure and stroke, particularly with longer durations of LT3 therapy (≥52 weeks).

The increased risks were especially notable in LT3 users with a history of thyroid cancer, suggesting that clinicians should carefully evaluate the long-term safety of LT3 therapy in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart Failure and Stroke Risks in Users of Liothyronine With or Without Levothyroxine Compared with Levothyroxine Alone: A Propensity Score-Matched Analysis. Yi, W., Kim, BH., Kim, M., et al.[2022]

In a study of 737 patients with acute first-ever stroke, 56% had low triiodothyronine (T3) levels, which were associated with a higher 1-year mortality rate of 27.34% compared to 19.37% for those with normal T3 levels.

Low T3 levels were also linked to a lower likelihood of independence after one year, with only 54.2% of low T3 patients achieving independence compared to 68.7% of those with normal T3, indicating that low T3 is a significant predictor of both survival and functional outcomes post-stroke.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low triiodothyronine: a strong predictor of outcome in acute stroke patients. Alevizaki, M., Synetou, M., Xynos, K., et al.[2022]

Low triiodothyronine syndrome (LT3S) occurs in 23.3% of patients with acute myocardial infarction (AMI) and is associated with more severe myocardial injury, as indicated by higher levels of cardiac troponin I and N-terminal pro-brain natriuretic peptide.

Patients with LT3S have a significantly higher rate of in-hospital cardiovascular death (4.7% vs. 1.7%) compared to those without LT3S, and incorporating LT3S into the TIMI risk score improves the predictive accuracy for in-hospital cardiovascular death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low T3 syndrome improves risk prediction of in-hospital cardiovascular death in patients with acute myocardial infarction. Su, W., Zhao, XQ., Wang, M., et al.[2019]

In a study of 50 heart failure patients with low-triiodothyronine syndrome, those receiving liothyronine therapy showed a significant improvement in exercise capacity, as measured by a 6-minute walk distance increase of 93 meters compared to 67 meters in the placebo group.

Liothyronine therapy also led to notable reductions in inflammatory markers and improved heart function, evidenced by decreased levels of N-terminal pro-brain natriuretic peptide and an increase in left ventricular ejection fraction, indicating its potential safety and efficacy in managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of triiodothyronine replacement therapy in patients with chronic stable heart failure and low-triiodothyronine syndrome: a randomized, double-blind, placebo-controlled study. Amin, A., Chitsazan, M., Taghavi, S., et al.[2021]

Supplementation with low and replacement doses of triiodothyronine (T3) improved cardiac function and metabolic profiles in an animal model of heart failure with preserved ejection fraction (HFpEF), particularly with the higher dose leading to normal myocardial T3 levels.

While low-dose T3 was safe and well-tolerated, the replacement dose increased heart rate and risk of arrhythmias, highlighting the need for careful management of T3 levels in HFpEF treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Triiodothyronine Treatment in an Animal Model of Heart Failure with Preserved Ejection Fraction. Neves, JS., Leite, AR., Conceição, G., et al.[2023]

In a study of 37 patients with acute myocardial infarction and low T3 syndrome, T3 replacement therapy was found to be safe, with no signs of hyperthyroidism or arrhythmias, and resulted in significant increases in fT3 levels.

T3-treated patients showed greater improvements in heart function, including a significant reduction in wall motion score index and an increase in stroke volume compared to untreated patients, indicating that T3 therapy can enhance recovery after a heart attack.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Usefulness of Triiodothyronine Replacement Therapy in Patients With ST Elevation Myocardial Infarction and Borderline/Reduced Triiodothyronine Levels (from the THIRST Study). Pingitore, A., Mastorci, F., Piaggi, P., et al.[2019]

Citations

1. isrctn.com isrctn.com/pdf/10706683

The use of thyroid hormone liothyronine in patients with ... Of these, two have demonstrated that T3 is effective and safe in improving left ventricular function whereas the third failed to reach. [_] Prospectively ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5746964/

Effects of triiodothyronine replacement therapy in patients ... Triiodothyronine replacement by chronic liothyronine therapy seems to safely benefit stable HF patients with LT3S receiving optimal HF medications. Keywords: ...

3. ahajournals.org ahajournals.org/doi/10.1161/circ.150.suppl_1.4147079

Abstract 4147079: Effects of Oral LT3 in Participants with ... After LT3 treatment, T3 levels markedly increased compared with placebo. Heart rate was higher on LT3 (mean difference 2.4 beats per minute, p < ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1530891X22005638

Review Article The Effectiveness of Thyroid Hormone ... This meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome.

5. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/16/NCT04112316/Prot_SAP_000.pdf

developing oral lt3 therapy for heart failure (dot3hf) We will simultaneously investigate the safety, feasibility, and preliminary efficacy of thyroid hormone therapy (LT3) in individuals diagnosed ...

6. academic.oup.com academic.oup.com/jcem/article/110/11/3278/8227161

Risk of Death and Adverse Effects in Patients on Liothyronine A large cohort study from Korea reported an increased risk of heart failure and strokes among LT3 users compared to LT4 users (79). This study, however, ...

7. journals.sagepub.com journals.sagepub.com/doi/full/10.1089/thy.2021.0634

Heart Failure and Stroke Risks in Users of Liothyronine ... However, we found that long-term use of LT3 was associated with increased incidence of heart failure in patients with a history of thyroid cancer and increased ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40795305/

Risk of death and adverse effects in patients on Liothyronine Our findings are reassuring that regulated LT3 use is not associated with risk of death or serious adverse outcomes.