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

Trial Summary

What is the purpose of this trial?

Hypothyroidism is a common condition, more frequent in females, associated with excess of cardiovascular risk and poor quality of life not completely abrogated by treatment with levothyroxine. There is an unmet need to define a safe, effective, and feasible regimen to be applied in large trials aimed at assessing levothyroxine/liothyronine combination therapy in patients living with hypothyroidism. To address this knowledge gap we propose a randomized, three-arm, double-blind, controlled, escalating dose parallel pilot study whose results will lay the foundation of large multicenter trial(s) able to demonstrate the effectiveness (or lack thereof) of levothyroxine/liothyronine combination therapy.

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.

What data supports the effectiveness of the drug Levothyroxine/Liothyronine for hypothyroidism?

Some studies suggest that combining levothyroxine (LT4) and liothyronine (LT3) may improve patient preference and symptoms in hypothyroidism compared to levothyroxine alone, although the evidence is not consistent across all measures. ^{1 2 3 4 5}

Is the combination therapy of levothyroxine and liothyronine safe for humans?

The combination therapy of levothyroxine and liothyronine has been evaluated in several studies, with some reporting increased adverse reactions compared to levothyroxine alone. The long-term safety profile of liothyronine remains uncertain, and more research is needed to fully understand its safety. ^{1 4 6 7 8}

How is the Levothyroxine/Liothyronine drug different from other hypothyroidism drugs?

The Levothyroxine/Liothyronine drug combines two synthetic thyroid hormones, T4 and T3, which some studies suggest may improve mood and quality of life more than Levothyroxine alone, although this remains controversial and not widely accepted as standard treatment. ^{1 3 5 7 9}

Research Team

Francesco Celi

Principal Investigator

UConn Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Canada 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. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. [2022]

4. United States 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. [2022]

5. Brazil pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Combination Thyroid Hormone Replacement; Knowns and Unknowns. [2019]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

Is combination therapy appropriate for hypothyroidism? [2016]

9. Netherlands pubmed.ncbi.nlm.nih.gov

LT4 and Slow Release T3 Combination: Optimum Therapy for Hypothyroidism? [2022]