Levothyroxine Dosing for Hypothyroidism in Older Adults

(DOT4 Trial)

Overseen By Theresa M. Scattergood, M.S.N., R.N.

Age: 65+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of Pennsylvania

Must be taking: LT4

Must not be taking: LT3, Thyroid extracts

Disqualifiers: Hypopituitarism, Thyroid cancer, GFR <30, 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 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

228 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how different doses of Levothyroxine, a common thyroid medication, affect older adults with hypothyroidism, a condition where the thyroid gland doesn't produce enough hormones. It compares two groups: one with a lower target TSH level (a hormone that regulates thyroid function) and another with a higher target TSH level. Individuals aged 65 or older, diagnosed with hypothyroidism for at least six months, and on stable Levothyroxine doses might be suitable candidates. The goal is to determine if adjusting the dose can improve health outcomes in older adults. As a Phase 4 trial, this research aims to understand how this FDA-approved and effective treatment can benefit more patients.

Will I have to stop taking my current medications?

If you are currently taking liothyronine (LT3), thyroid extracts, Tirosint liquid or capsules, or medications that interfere with thyroid function, you will need to stop taking them to participate in the trial.

What is the safety track record for Levothyroxine Sodium?

Research has shown that levothyroxine, a common treatment for low thyroid levels, carries some risks, particularly for older adults. Studies have found that using this thyroid hormone in older adults might increase the risk of death by 60% each year, highlighting the importance of careful dosage management.

Some patients have experienced problems from excessive levothyroxine, which can occur if the dose is too high, leading to unwanted side effects. As people age, their need for levothyroxine may decrease, increasing the risk of overmedication.

Conversely, other studies suggest that levothyroxine doesn't always alleviate thyroid-related symptoms in older adults. Therefore, monitoring and adjusting the dose carefully is crucial to ensure safety. Consulting healthcare providers is essential to tailor the treatment plan to each individual. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about exploring levothyroxine dosing for hypothyroidism in older adults because it aims to tailor treatment more precisely to this age group’s unique needs. Unlike the standard approach that typically targets a low TSH level (0.5-2.0 mU/L), this trial also examines the effects of maintaining a higher TSH level (5.5-7.0 mU/L). This could lead to more personalized treatment plans, potentially reducing side effects and improving quality of life for older adults. By investigating these different TSH targets, researchers hope to find the optimal balance between symptom control and overall health in older patients.

What is the effectiveness track record for Levothyroxine Sodium in treating hypothyroidism in older adults?

Research has shown that levothyroxine effectively treats overt hypothyroidism, a condition where the thyroid gland doesn't produce enough hormones. Levothyroxine helps many patients achieve desired thyroid-stimulating hormone (TSH) levels, improving their symptoms. This trial will compare two dosing strategies for levothyroxine in older adults with subclinical hypothyroidism: one targeting a lower TSH level (0.5-2.0 mU/L) and another targeting a higher TSH level (5.5-7.0 mU/L). Studies have found that levothyroxine may not significantly improve symptoms in subclinical cases, but it is often used because it can help regulate hormone levels, which is important for managing more severe thyroid issues. Therefore, while levothyroxine is effective for overt hypothyroidism, its benefits for mild cases remain less certain. ^{1 5 6 7 8}

Who Is on the Research Team?

Anne R. Cappola, M.D., Sc.M.

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for community-dwelling individuals aged 65 or older who have been diagnosed with hypothyroidism for at least 6 months, are on a stable dose of Levothyroxine Sodium (75-200 mcg per day), and can take oral medication. They must be able to follow the study procedures throughout its duration. People with hypopituitarism, history of thyroid cancer requiring TSH suppression, severe kidney issues (GFR <30), or those taking certain thyroid medications cannot participate.

Inclusion Criteria

I am 65 years or older and live in a community setting.

I can take pills and will follow the medication schedule.

Provision of signed and dated informed consent form

Exclusion Criteria

I have been diagnosed with hypopituitarism.

I have had thyroid cancer and need treatment to lower my TSH levels.

Other conditions which, in the opinion of the investigators, would prevent them from participating in the full duration of the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of two 6-month dosing strategies of levothyroxine (LT4) to maintain different target TSH levels

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 Sodium

Trial Overview

The trial aims to explore the effects of more flexible dosing schedules of Levothyroxine Sodium (LT4) in older adults with hypothyroidism. It will assess how different dosing regimens might impact overall health and management of the condition.

How Is the Trial Designed?

Group I: Higher TSH group Experimental Treatment 1 Intervention

Target TSH level of 5.5-7.0 mU/L

Group II: Lower TSH Group Active Control 1 Intervention

Target TSH level of 0.5-2.0 mU/L

Levothyroxine Sodium is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in United States as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer
• Goiter

Approved in Canada as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in Japan as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in China as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Approved in Switzerland as Levothyroxine Sodium for:

• Hypothyroidism
• Thyroid nodules
• Thyroid cancer

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Published Research Related to This Trial

Levothyroxine sodium is the preferred treatment for most patients with hypothyroidism, providing stable hormone levels without daily fluctuations, and optimal dosing is guided by maintaining a TSH level of 1-2 mU/L.

In younger patients, starting with a near full dose of levothyroxine is effective, while older patients or those with coronary artery disease should begin with a lower dose to minimize risks of cardiac events and osteoporosis from over-replacement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing treatment of hypothyroidism. Clarke, N., Kabadi, UM.[2019]

Levothyroxine Sodium is an important thyroid hormone replacement therapy for hypothyroidism and has various applications, including treating goiters and certain thyroid cancers, highlighting its efficacy in managing thyroid-related conditions.

Recent patents have focused on improving the stability and formulation of Levothyroxine Sodium due to challenges like photosensitivity and oxidation, which could lead to better and more cost-effective treatments in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levothyroxine Sodium - Thyroid Hormone Replacement Therapy for Hypothyroidism: A Review of Patent Literature. Upadhyay, U., Vora, PA., Patel, R., et al.[2023]

Hypothyroidism in older adults can significantly impact their health, cognitive function, and quality of life, necessitating careful management and treatment decisions.

Levothyroxine is the recommended treatment, starting at low doses (12.5 mcg to 25 mcg) and adjusted every 6 weeks, with attention to potential interactions with other medications and foods, emphasizing the importance of using consistent brand-name formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypothyroidism: challenges when treating older adults. Pearson, T.[2013]

Liquid levothyroxine (LT4) formulations, particularly Tirosint SOL, are more effective than tablet forms for patients with malabsorption issues, leading to better hormonal control and less frequent TSH measurements.

The liquid LT4 is safe and effective for various populations, including newborns and pregnant women, but caution is needed in neonates due to a higher risk of TSH suppression compared to tablet LT4.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expert opinion on liquid L-thyroxine usage in hypothyroid patients and new liquid thyroxine formulation - Tirosint SOL [Opinia ekspertów dotycząca stosowania płynnej postaci lewotyroksyny oraz nowego preparatu Tirosint SOL u chorych na niedoczynność tarczycy]. Gietka-Czernel, M., Hubalewska-Dydejczyk, A., Kos-Kudła, B., et al.[2021]

The new formulation of levothyroxine (L-T4) has been shown to be bioequivalent to the current formulation, with a geometric mean ratio of 99.3% for the area under the curve (AUC) and 101.7% for maximum concentration (Cmax), ensuring consistent therapeutic effects.

This reformulated L-T4 meets strict potency specifications and demonstrates dosage form proportionality, allowing for more precise dosing tailored to individual patient needs, which enhances safety in thyroid hormone management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials. Gottwald-Hostalek, U., Uhl, W., Wolna, P., et al.[2018]

In a study of 11 elderly hypothyroid patients, a gradual increase in levothyroxine sodium dosage led to effective normalization of thyroid hormone levels, with a mean effective dose of 110 micrograms per day.

The findings suggest that the required levothyroxine replacement dose for elderly patients is about one-third lower than previously recommended, indicating a need for adjusted dosing in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimation of a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. Davis, FB., LaMantia, RS., Spaulding, SW., et al.[2013]

Levothyroxine sodium (LT4) is the primary treatment for hypothyroidism, aiming to achieve normal thyroid-stimulating hormone (TSH) levels, with dosages typically starting at 50-100 micrograms for adults without heart disease risk, and lower for older patients or those at risk.

Regular monitoring of TSH levels is crucial after establishing the appropriate LT4 dose, with evaluations starting at six months and continuing annually, to ensure effective management of the condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of hypothyroidism]. Massol, J.[2013]

A 49-year-old woman with refractory hypothyroidism did not respond to high doses of oral levothyroxine (LT4) due to malabsorption linked to Helicobacter pylori gastritis, highlighting the importance of assessing gastrointestinal health in such cases.

Switching from oral LT4 tablets to a liquid formulation resulted in significant clinical and biological improvement, suggesting that patients with absorption issues may benefit from alternative LT4 delivery methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levothyroxine liquid oral substitution as an alternative treatment for refractory hypothyroidism due to gastrointestinal malabsorption: A case report. Cherchir, F., Oueslati, I., Mouelhi, Y., et al.[2023]

In a study of 19 hypothyroid patients switching from tablet to softgel levothyroxine (LT4), 88.9% achieved TSH levels below 4.0 mIU/L after 3 months, indicating improved thyroid function with the softgel formulation.

The median TSH level significantly decreased from 3.33 mIU/L on tablet LT4 to 1.90 mIU/L on softgel LT4, suggesting that softgel LT4 may enhance bioavailability and effectiveness in patients without malabsorption issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thyroxine Treatment With Softgel Capsule Formulation: Usefulness in Hypothyroid Patients Without Malabsorption. Trimboli, P., Virili, C., Centanni, M., et al.[2022]

In a study of 21 hypothyroid patients, switching from levothyroxine (L-T4) tablets to a liquid formulation significantly improved thyroid-stimulating hormone (TSH) levels, bringing them into the normal range within 2 months.

When patients who had switched back to tablets experienced a rise in TSH levels, it indicated that the liquid L-T4 formulation is more effective for controlling TSH levels in patients without malabsorption or drug interference.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IN PATIENTS WITH SUBCLINICAL HYPOTHYROIDISM WHILE IN THERAPY WITH TABLET L-T4, THE LIQUID L-T4 FORMULATION IS MORE EFFECTIVE IN RESTORING EUTHYROIDISM. Fallahi, P., Ferrari, SM., Antonelli, A.[2022]

Switching from levothyroxine (LT4) tablets to an oral solution (LT4-OS) significantly decreased serum TSH levels in hypothyroid patients, indicating improved absorption, with a median TSH reduction from 3.04 to 2.30 μIU/mL.

In the study of 53 patients, 67.9% experienced a decrease in TSH levels after the switch, particularly those with factors that typically interfere with LT4 absorption, suggesting LT4-OS may be more effective for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of TSH Levels with Liquid Formulation Versus Tablet Formulations of Levothyroxine in the Treatment of Adult Hypothyroidism. Brancato, D., Scorsone, A., Saura, G., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8006441/

Levothyroxine Therapy in Elderly Patients With Hypothyroidism

Levothyroxine (L-T4) treatment of overt hypothyroidism can be more challenging in elderly compared to young patients.

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8799578/

Comparative Effectiveness of Persistent Use of a Name- ...

This real-world data study showed Synthroid was associated with better TSH target achievement vs. GL in a US managed care population.

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1603825

Thyroid Hormone Therapy for Older Adults with Subclinical ...

We found that levothyroxine had no consistent beneficial effect on thyroid-related symptoms. This finding was true in both older men and older ...

4.

ccjm.org

ccjm.org/content/92/4/221

Most elderly patients with subclinical hypothyroidism do not ...

Studies have not found levothyroxine replacement therapy to make any significant clinical difference in most cases of mild subclinical ...

5.

jamanetwork.com

jamanetwork.com/journals/jamanetworkopen/fullarticle/2776099

Effect of Levothyroxine Therapy on the Development ...

This ancillary study of a randomized clinical trial found no effect of levothyroxine therapy on the development of depressive symptoms in older ...

6.

endocrine.org

endocrine.org/news-and-advocacy/news-room/2020/thyroid-hormone-use-may-raise-death-risk-in-older-adults

Thyroid hormone use may raise death risk in older adults

They found that among older adults, use of thyroid hormone increased risk of death 60% year over year (hazard ratio 1.6).

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10151847/

Effects of discontinuation of levothyroxine treatment in ...

First, the physical need for levothyroxine can decrease with age thereby posing a higher risk of overtreatment and adverse effects. Second, ...

8.

jamanetwork.com

jamanetwork.com/journals/jama/fullarticle/2753909

Levothyroxine Treatment and Thyroid-Related Symptoms ...

In a 2017 clinical randomized trial of 737 participants aged 65 years and older, treatment with levothyroxine demonstrated no benefit on the ...