Levothyroxine Dosing for Hypothyroidism in Older Adults

(DOT4 Trial)

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

Age: 65+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Recruiting

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

Prior Safety Data

Approved in 6 Jurisdictions

Trial Summary

What is the purpose of this trial?

Our overall goal is to determine the clinical consequences of allowing greater flexibility in LT4 dosing in older individuals who take LT4.

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 data supports the effectiveness of the drug Levothyroxine Sodium for treating hypothyroidism in older adults?

Levothyroxine Sodium is the preferred treatment for managing hypothyroidism, aiming to maintain normal thyroid hormone levels. It is effective in treating various thyroid-related conditions, including hypothyroidism, and is available in different formulations like tablets and liquid, which can be beneficial for patients with absorption issues. ^{1 2 3 4 5}

Is Levothyroxine safe for older adults with hypothyroidism?

Levothyroxine is generally safe for humans, including older adults, when used at the appropriate dose. However, starting with a low dose and gradually increasing it is recommended for older patients or those with heart disease to avoid potential heart-related issues. Chronic overuse can lead to bone thinning, especially in postmenopausal women. ^{1 4 6 7 8}

How is the drug Levothyroxine Sodium unique in treating hypothyroidism in older adults?

Levothyroxine Sodium is unique because it requires careful dosing adjustments in older adults, starting at lower doses and increasing slowly to avoid complications, especially in those with heart disease. Additionally, it is important to use a consistent brand due to variations in generic formulations, and a liquid form may be beneficial for those with absorption issues. ^{1 4 9 10 11}

Research Team

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

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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.

I understand and can follow the study's requirements.

Trial Timeline

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

Treatment Details

Interventions

• Levothyroxine Sodium (Hormone Therapy)

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.

Participant Groups

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 Canada, Japan, China, Switzerland for the following indications:

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+

Dr. Joan Lau

University of Pennsylvania

Chief Executive Officer since 2020

PhD in Neuroscience from the University of Cincinnati College of Medicine, MBA from the Wharton School of Business, BS in Bioengineering from the University of Pennsylvania

Dr. Robert Iannone

University of Pennsylvania

Chief Medical Officer since 2019

MD from Yale University, MSCE from the University of Pennsylvania

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

Dr. Richard J. Hodes

National Institute on Aging (NIA)

Chief Executive Officer since 1993

MD from Harvard Medical School

Dr. Marie Bernard

National Institute on Aging (NIA)

Chief Medical Officer

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Levothyroxine Sodium - Thyroid Hormone Replacement Therapy for Hypothyroidism: A Review of Patent Literature. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Thyroxine Treatment With Softgel Capsule Formulation: Usefulness in Hypothyroid Patients Without Malabsorption. [2022]

3. United States 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. [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Treatment of hypothyroidism]. [2013]

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

Comparison of TSH Levels with Liquid Formulation Versus Tablet Formulations of Levothyroxine in the Treatment of Adult Hypothyroidism. [2022]

6. Poland 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]. [2021]

7. England pubmed.ncbi.nlm.nih.gov

New levothyroxine formulation meeting 95-105% specification over the whole shelf-life: results from two pharmacokinetic trials. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Optimizing treatment of hypothyroidism. [2019]

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

Hypothyroidism: challenges when treating older adults. [2013]

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

Estimation of a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. [2013]

11. England pubmed.ncbi.nlm.nih.gov

Levothyroxine liquid oral substitution as an alternative treatment for refractory hypothyroidism due to gastrointestinal malabsorption: A case report. [2023]