Novel Treatments for Hypothyroidism

Overseen By Mallory Edrich, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: UConn Health

Must be taking: Levothyroxine

Must not be taking: T3 therapies, Semaglutide

Disqualifiers: Pregnancy, Diabetes, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for people with hypothyroidism, a condition where the thyroid gland doesn't produce enough hormones, affecting daily life and heart health. The study tests a combination of two medications, levothyroxine and liothyronine (synthetic thyroid hormones), to determine if they work better together than levothyroxine alone. Participants will be divided into three groups: one receiving only levothyroxine, another receiving the combination once daily, and the last receiving the combination twice daily. The trial seeks individuals treated with levothyroxine at a dose of more than 1.2 mcg/kg, without certain other health conditions like uncontrolled diabetes or high blood pressure. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial requires that you continue taking your current levothyroxine medication. If you are on lipid-lowering or anti-acid medications, you must keep the same dose throughout the study. Other medications that interfere with thyroid hormone absorption may exclude you from participating.

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

Research has shown mixed safety results for using a combination of levothyroxine and liothyronine to treat low thyroid levels. Some studies found this combination safe for a small group of people with thyroid cancer who had low thyroid levels after surgery. However, other evidence suggests that the safety of liothyronine remains uncertain for some patients.

Many people prefer this combination treatment, but its safety and benefits are still under investigation. While some have experienced positive outcomes with the combination therapy, others might not. Always consult a doctor about any concerns before starting a new treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for hypothyroidism because they explore the potential benefits of combining levothyroxine with liothyronine, which is not a typical standard of care. Most treatments for hypothyroidism primarily use levothyroxine alone, which replaces the hormone thyroxine. However, the combination therapies being studied include liothyronine, a form of triiodothyronine (T3), which may offer more balanced hormone replacement. One combination therapy administers liothyronine once daily, while the other does so twice daily, allowing researchers to investigate optimal dosing strategies for improved patient outcomes. This approach could lead to better symptom management for patients who don't fully respond to levothyroxine alone.

What evidence suggests that this trial's treatments could be effective for hypothyroidism?

Research shows that many people with an underactive thyroid continue to experience symptoms even when taking levothyroxine alone. In this trial, one group of participants will receive only levothyroxine, while others will receive a combination therapy of levothyroxine and liothyronine, with liothyronine administered either once or twice daily. Studies suggest that adding liothyronine to levothyroxine can improve symptoms for some individuals. Some patients have reported feeling better after switching to this combined treatment. This combination may also help balance thyroid hormone levels and lower cholesterol. While these results are promising, individual responses can vary, and more research is needed to confirm these findings. ^{3 5 6 7 8}

Who Is on the Research Team?

Francesco Celi

Principal Investigator

UConn Health

Are You a Good Fit for This Trial?

This trial is for individuals with hypothyroidism, particularly more common in females. It aims to find a better treatment regimen than the current standard. Participants should be willing to try new combinations of thyroid medications and adhere to the study protocol.

Inclusion Criteria

I have a history of hypothyroidism.

I take more than 1.2 mcg/kg of Levothyroxine daily.

I am taking levothyroxine.

Exclusion Criteria

I am currently taking medication that contains T3.

Pregnancy

Breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either Levothyroxine alone, Levothyroxine/Liothyronine with Liothyronine once daily, or Levothyroxine/Liothyronine with Liothyronine twice daily for six months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Levothyroxine/Liothyronine

Trial Overview The study tests three different treatments: standard Levothyroxine, a combination of Levothyroxine/Liothyronine taken once daily, and the same combination taken twice daily. The goal is to determine which regimen improves quality of life and reduces cardiovascular risks.

How Is the Trial Designed?

Group I: Combination therapy liothyronine twice daily Experimental Treatment 2 Interventions

Patients in this arm will be administered Levothyroxine/Liothyronine with Liothyronine administered twice daily.

Group II: Combination therapy liothyronine once daily Experimental Treatment 2 Interventions

Patients in the arm will be administered Levothyroxine/Liothyronine with Liothyronine administered once daily plus placebo

Group III: Levothyroxine alone Active Control 1 Intervention

Patients in this arm will be administered Levothyroxine/Placebo

Levothyroxine/Liothyronine is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Levothyroxine/Liothyronine for:

• Hypothyroidism
• Thyroid hormone replacement therapy

Approved in United States as Levothyroxine/Liothyronine for:

• Hypothyroidism
• Thyroid hormone replacement therapy

Approved in Canada as Levothyroxine/Liothyronine for:

• Hypothyroidism
• Thyroid hormone replacement therapy

Who Is Running the Clinical Trial?

UConn Health

Lead Sponsor

Trials

218

Recruited

59,100+

Published Research Related to This Trial

Levothyroxine is the preferred treatment for hypothyroidism, as combination therapy with liothyronine has shown limited benefits and increased adverse reactions in most studies.

Only one study indicated positive outcomes with the combination therapy, highlighting the need for more rigorous trials with larger, more uniform participant groups to assess its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is combination therapy appropriate for hypothyroidism? Linder, LM., Clements, JN.[2016]

A study involving 46 patients with primary hypothyroidism found that adding liothyronine to levothyroxine did not lead to significant improvements in health-related quality of life or cognitive performance compared to levothyroxine alone.

Both treatment groups showed similar serum thyrotropin levels, body weight, and serum lipid levels, indicating that the combination therapy did not provide additional benefits over standard levothyroxine treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. Clyde, PW., Harari, AE., Getka, EJ., et al.[2022]

In a study of 141 patients with primary autoimmune hypothyroidism, those receiving a combination of levothyroxine (LT4) and liothyronine (LT3) reported higher satisfaction with their treatment compared to those on LT4 alone, with preference rates of 29.2% for LT4, 41.3% for LT4/LT3 at a 10:1 ratio, and 52.2% for LT4/LT3 at a 5:1 ratio.

Despite the increased preference for the combination therapy, there were no significant differences in mood, fatigue, or neurocognitive function among the treatment groups, suggesting that the preference may be linked to weight loss associated with the combination therapy rather than improved overall health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. Appelhof, BC., Fliers, E., Wekking, EM., et al.[2022]

In a study of 32 adults with primary hypothyroidism, the fixed combination therapy of levothyroxine/liothyronine (LT4/LT3) resulted in significantly lower free T4 levels compared to standard LT4 treatment, but did not affect TSH or T3 levels.

Despite some patients on LT4/LT3 experiencing elevated T3 levels and an increased heart rate, the combination therapy did not show clear clinical benefits in terms of lipid profile, body weight, or quality of life, suggesting that further research is needed to explore its efficacy in specific populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. Kaminski, J., Miasaki, FY., Paz-Filho, G., et al.[2023]

A systematic review of 13 clinical practice guidelines from various regions found that the standard treatment for hypothyroidism is levothyroxine (LT4) alone, with no strong evidence supporting the routine use of combination therapy with liothyronine (LT3).

Only two guidelines suggested that combination therapy could be considered in specific circumstances, indicating that while there is some interest in LT4 and LT3 combination therapy, it is not widely endorsed as a standard treatment for hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review of Clinical Practice Guidelines' Recommendations on Levothyroxine Therapy Alone versus Combination Therapy (LT4 plus LT3) for Hypothyroidism. Kraut, E., Farahani, P.[2022]

Combined treatment with levothyroxine and liothyronine for hypothyroidism has shown potential benefits in mood, quality of life, and psychometric performance in some studies, suggesting it may be preferred by patients over levothyroxine alone.

Despite these potential benefits, the addition of liothyronine could lead to adverse events, and until more clear advantages are established, levothyroxine alone remains the recommended treatment for hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. Escobar-Morreale, HF., Botella-Carretero, JI., Morreale de Escobar, G.[2015]

Current evidence suggests that combining T(3) and T(4) treatment may improve quality of life and cognitive function in hypothyroid patients, indicating a potential shift from traditional levothyroxine therapy alone.

The review highlights the need for personalized thyroid hormone replacement regimens and calls for further randomized controlled studies to explore the benefits and optimal ratios of T(4) and T(3) in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? Biondi, B., Wartofsky, L.[2022]

Levothyroxine (LT4) monotherapy can lead to higher levels of serum free T4 but lower levels of free T3 in some patients, which may not fully alleviate symptoms of hypothyroidism.

While LT4 combined with LT3 therapy can increase serum T3 levels and improve hormone ratios, it does not significantly enhance overall outcomes like quality of life or mental health compared to LT4 alone, and the long-term safety of this combination remains uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LT4 and Slow Release T3 Combination: Optimum Therapy for Hypothyroidism? Azizi, F., Amouzegar, A., Mehran, L., et al.[2022]

Levothyroxine monotherapy is the standard and effective treatment for hypothyroidism, but 10-15% of patients still report dissatisfaction with their health, leading some to consider adding liothyronine for better results.

Current clinical trials have not shown that combining levothyroxine with liothyronine is superior to using levothyroxine alone, indicating a need for more research, particularly randomized controlled trials, to explore the long-term safety and efficacy of combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Thyroid Hormone Replacement; Knowns and Unknowns. Taylor, PN., Eligar, V., Muller, I., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8566135/

T4+T3 Combination Therapy: An Unsolved Problem of ... In the early 2000s, persistent symptoms despite a normal TSH were reported by 5% to 15% of hypothyroid patients on LT4 treatment [5,6]. One may ask whether ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2214624525000206

Combination Therapy with Levothyroxine and Liothyronine ... This case series describes three patients who improved after switching to combination therapy with levothyroxine and liothyronine. These ...

3. etj.bioscientifica.com etj.bioscientifica.com/view/journals/etj/14/2/ETJ-24-0275.xml

Long-term outcomes of LT4/LT3 combination treatment for ... Population-based studies have shown that 34% of LT4-treated hypothyroid patients have a decreased quality of life (QoL) compared to 26% of the general ...

4. bmcendocrdisord.biomedcentral.com bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-024-01612-6

Evaluating the effectiveness of combined T4 and T3 therapy or ... Our study revealed that combined therapy and DTE lead to higher T3 and lower T4 levels, compared to T4 monotherapy in hypothyroidism.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06731764

Novel Approaches to the Treatment of Hypothyroidism The data suggest that LT4/LT3 combination therapy is effective in normalizing thyroid hormone levels and in preventing the rise in serum cholesterol and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7983670/

Evidence-Based Use of Levothyroxine/Liothyronine ... Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3).

7. thyroid.org thyroid.org/patient-thyroid-information/ct-for-patients/march-2024/vol-17-issue-3-p-13-14/

Safety of levothyroxine plus liothyronine (T4/T3) therapy in ... This study shows that the combination T4/T3 therapy was safe in this small group of thyroid cancer patients with post-surgical hypothyroidism.

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

Risk of Death and Adverse Effects in Patients on Liothyronine Although some patients with hypothyroidism prefer combination therapy with liothyronine (LT3) and levothyroxine (LT4), the safety of LT3 remains unresolved.