T4/T3 Therapy in Hypothyroidism

This study will test whether 6 months of combination therapy with levothyroxine (LT4) plus liothyronine (LT3) is superior to LT4 plus placebo in participants with hypothyroidism who have residual symptoms of hypothyroidism with TSH levels within the reference range.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypothyroidism Primary
• Intervention / Treatment: Drug: Liothyronine (L-T3); Drug: Levothyroxine Sodium (LT4) Tablets; Drug: Liothyronine (LT3) placebo

Detailed Description

.Participants will

• Take LT4+LT3 or LT4+placebo for 6 months
• Visit the clinic at the beginning and the end of the study for a blood test and to answer questionnaires.
• Have blood tests checked at 6 and 13 weeks and symptom checks by text (weekly to monthly)

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Anne R. Cappola, MD, ScM; Phone Number: 215-573-5359; Email: acappola@pennmedicine.upenn.edu
• Study Contact Backup: Name: Theresa Scattergood, MSN, RN; Phone Number: 215-898-5664; Email: theresa.scattergood@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine, Smilow Center for Translational Resarch,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female, aged 18-70 years
2. Hypothyroidism due to either thyroid failure or total thyroidectomy for structural thyroid disease (nodules, benign goiter, or thyroid cancer) for at least 6 months
3. Taking 75-150 mcg per day LT4 and a minimum of 1.2 mcg/kg/day, with stable dose of LT4 for at least 3 months prior to enrollment
4. TSH of 0.5 to 4.0 mU/L within 2 months of enrollment
5. Persistent symptoms for at least 2 months, and a TSQ score of ≥ 5
6. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 4 weeks after the end of study intervention.

Exclusion Criteria:

1. Current use of LT3, thyroid extracts, Tirosint liquid or capsules, amiodarone, lithium, methimazole, propylthiouracil, supraphysiologic doses of corticosteroids, immunotherapy, tyrosine kinase inhibitors, interferon, or biotin supplements
2. Diseases of the pituitary or hypothalamus
3. History of thyroid cancer requiring suppression of TSH secretion
4. Unstable cardiac conditions, including uncontrolled hypertension (current blood pressure greater than 160/100), arrhythmia, or angina
5. Uncontrolled psychiatric disorders
6. Pregnancy or lactation, or planned pregnancy within the next 7 months
7. History of food dye allergies
8. GFR <30 ml/min/1.73 m2
9. Other conditions which, in the opinion of the investigators, would prevent them from participating in the full duration of the study (for example, end-stage cancer)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LT4+LT3; Levothyroxine plus liothyronine therapy	Drug: Liothyronine (L-T3); Participants will either take LT3 with an LT4 dose that is reduced from baseline or they will take liothyronine placebo with their baseline LT4 dose.; Drug: Levothyroxine Sodium (LT4) Tablets; All participants will take levothyroxine.
Active Comparator: LT4+placebo; Levothyroxine plus liothyronine placebo	Drug: Levothyroxine Sodium (LT4) Tablets; All participants will take levothyroxine.; Drug: Liothyronine (LT3) placebo; Identical placebo tablet without containing liothyronine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ThyPRO Composite QOL Scale	22 items, scored 0-100, higher scores indicate worse status	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pittsburgh Sleep Quality Index	19 items, range of 0-21, higher scores indicate worse sleep	6 months
ThyPRO subscales	ThyPRO hypothyroid symptoms and tiredness subscales, 4 items, scored 0-100, higher scores indicate worse status	6 months
Thyroid Symptoms Questionnaire (TSQ)	Thyroid symptoms scale, 12 items, score range 0-36, higher score indicates worse status	6 months
Cognitive measures	NIH Toolbox Fluid Cognition Score, based around median of 100, higher scores indicate higher function	Baseline and 6 months
Beck Depression Inventory	21 items, range of 0-63, higher scores indicate more depressive symptoms	Baseline and 6 months
Beck Anxiety Inventory	21 items, range 0-63, higher scores indicate more anxiety	Baseline and 6 months
Weight	Kilograms	6 months
LDL cholesterol	Blood test, g/dL	6 months
Serum c-telopeptide	Blood test, pg/mL	6 months
Satisfaction with randomized status	Participants will be asked if they can guess their randomization status and satisfaction with randomized status	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom checks	Questionnaire of 4 hypothyroid symptoms, higher scores indicate worse function	Weekly for 8 weeks and at months 3, 4, and 5

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: February 6, 2026
• First Submitted That Met QC Criteria: February 13, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Hypothyroidism; levothyroxine; liothyronine
• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hypothyroidism; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Pharmaceutical Preparations; Dosage Forms; Amino Acids; Amino Acids, Aromatic; Amino Acids, Cyclic; Thyroid Hormones; Thyronines; Tablets; Thyroxine; Triiodothyronine
• Other Study ID Numbers: 10094647; R01DK137207 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

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