Novel Approaches to the Treatment of Hypothyroidism

March 17, 2026 updated by: Francesco Celi, UConn Health

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Hypothyroidism is a common condition associated with excess of cardiovascular risk and poor quality of life which are not completely abrogated by treatment with levothyroxine (synthetic T4, LT4), potentially because of the inability to compensate for the loss of T3 secreted by the thyroid gland. Experimental data in animal models indicate that only combination LT4 and liothyronine (synthetic T3, LT3) can restore normal concentrations of thyroid hormones across the tissues target of the hormonal action. Clinical trials based on LT4/LT3 combination therapy and desiccated thyroid extracts (containing T3) have provided conflicting data, but the plurality of the results indicates a preference toward T3-containing therapies when compared to LT4 alone. Conversely, the short half-life of T3 poses concern of cardiovascular toxicity due to fluctuating levels of T3, particularly when LT3 is prescribed in single dose. No study has systematically assessed the optimal dose and frequency of LT3 administration in LT4/LT3 combination therapy. There is an unmet need to define a safe, effective, and feasible regimen to be applied in large trials aimed at assessing LT4/LT3 therapy efficacy and safety.

We have conducted clinical studies aimed at characterizing the pharmacokinetics and pharmacodynamics of LT3 and, more recently, we completed a R21-sponsored LT4/LT3 combination therapy clinical trial in patients undergoing total thyroidectomy. The data suggest that LT4/LT3 combination therapy is effective in normalizing thyroid hormone levels and in preventing the rise in serum cholesterol and weight when compared to LT4 alone. Moreover, our results from a prior study appear to negate a clinical role of rapid T3 action, supporting the use of LT3 in single administration. These original findings serve as foundation for the current proposal.

Hypothesis: A once daily administration of LT4/LT3 combination therapy will be (i) effective yet safe, (ii) comparable to a twice daily LT4/LT3 administration regimen, and (iii) superior to LT4 therapy in improving clinically relevant indices of thyroid hormone action.

To test this hypothesis, we propose a randomized, three-arm, double-blind, controlled, escalating dose parallel pilot study in which 90 patients with hypothyroidism (30 each group) will be randomized to six months of treatment with LT4, LT4/LT3 with LT3 once daily, or LT4/LT3 with LT3 twice daily.

This novel and rigorous study based on our original observations will fill the knowledge gap of effects and dosing of LT4/LT3 combination therapy, laying the foundation for large multicenter trial(s) able to demonstrate the effectiveness (or lack thereof) of LT4/LT3 combination therapy, fulfilling the aims of PAS-23-086.

Study Type

Interventional

Enrollment (Estimated)

90

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Francesco S Celi, MD, MHSc.
  • Phone Number: (860) 679-2715
  • Email: celi@uchc.edu

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

History of hypothyroidism Treatment with levothyroxine Levothyroxine dose >1.2 mcg/kg

Exclusion Criteria:

Body weight <50 or >100 Kg.

Indication for TSH suppression (high risk follicular-derived thyroid cancer).

Secondary (pituitary) hypothyroidism (ICD-10 E23.0); Pregnancy; breastfeeding; uncontrolled diabetes (HbA1c >8.5% at screening); use of oral Semaglutide (Rybelsus); Uncontrolled Hypertension (BP > 140/90 at screening); current use of T3-containing therapies (Liothyronine, desiccated thyroid extracts).

Patients receiving lipid-lowering therapies must maintain the same dose throughout the participation in the study. Changes in lipid lowering therapy/dose will result in termination from the study.

Patients receiving anti-acid (H2 blockers, proton pump inhibitors) therapies must maintain the same dose throughout the participation in the study. Changes in anti-acid therapy/dose will result in termination from the study. Use of other medications known to interfere with the absorption of thyroid hormone, or affecting the thyroid hormone axis (Burch 2019) will be considered exclusion criteria.

Bariatric surgery, initiation of GLP-1 agonist therapy (irrespective of the indication), enrollment in structured weight loss programs will result in dismissal from the study.

Current pregnancy, pregnancy planned within the next 6 months, and lack of contraception in women of reproductive age will be exclusionary. We will verify that the participant is not pregnant through a urine pregnancy test at the time of the first study visit and at each of the follow-up visits. Any participants who become pregnant will terminate the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Levothyroxine alone
Patients in this arm will be administered Levothyroxine/Placebo
Drug: Levothyroxine

Patients will receive Levothyroxine/Placebo

Levothyroxine/Liothyronine with Liothyronine administered twice daily.

Other Names:
  • LT4
Experimental: Combination therapy liothyronine once daily
Patients in the arm will be administered Levothyroxine/Liothyronine with Liothyronine administered once daily plus placebo
Drug: Levothyroxine

Patients will receive Levothyroxine/Placebo

Levothyroxine/Liothyronine with Liothyronine administered twice daily.

Other Names:
  • LT4
Drug: Levothyroxine/Liothyronine once daily
Patients will receive Levothyroxine/Liothyronine with Liothyronine administered once daily;
Other Names:
  • LT4/LT3
Experimental: Combination therapy liothyronine twice daily
Patients in this arm will be administered Levothyroxine/Liothyronine with Liothyronine administered twice daily.
Drug: Levothyroxine

Patients will receive Levothyroxine/Placebo

Levothyroxine/Liothyronine with Liothyronine administered twice daily.

Other Names:
  • LT4
Drug: Levothyroxine/Liothyronine twice daily
Patients will receive Levothyroxine/Liothyronine with Liothyronine administered twice daily;
Other Names:
  • LT4/LT3

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Total Cholesterol
Time Frame: 6 month
Changes between groups
6 month
Changes in LDL Cholesterol
Time Frame: 6 month
Changes between groups
6 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Weight
Time Frame: 6 month
Changes between groups
6 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

UConn Health

Investigators

  • Principal Investigator: Francesco Celi, UConn Health

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 10, 2024

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

June 30, 2028

Study Registration Dates

First Submitted

December 9, 2024

First Submitted That Met QC Criteria

December 9, 2024

First Posted (Actual)

December 12, 2024

Study Record Updates

Last Update Posted (Actual)

March 19, 2026

Last Update Submitted That Met QC Criteria

March 17, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 24-186-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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