Dosing of LT4 in Older Individuals (DOT4)

Levothyroxine Dosing in Older Individuals

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

Study Overview

• Status: Recruiting
• Conditions: Hypothyroidism
• Intervention / Treatment: Drug: Levothyroxine Sodium

Detailed Description

Investigators will perform a randomized, parallel, double-blind clinical trial of two 6-month dosing strategies of levothyroxine (LT4) in patients aged 65 years and older who are already taking a stable dose of at least 1.2 mcg/kg/day of LT4 therapy, one to maintain a target thyroid stimulating hormone (TSH) level of 0.5-2.0 mU/L (lower TSH group) and another of a lower levothyroxine dose to achieve a target TSH of 5.5-7.0 mU/L (higher TSH group). Investigators will assess the effects of levothyroxine therapy at two different TSH targets on symptoms of hypothyroidism, mood, sleep, measures of memory and executive function, weight, lipids, and a marker of bone turnover.

• Study Type: Interventional
• Enrollment (Estimated): 228
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Anne R. Cappola, M.D., Sc.M.; Phone Number: 215-573-5359; Email: acappola@pennmedicine.upenn.edu
• Study Contact Backup: Name: Theresa M. Scattergood, M.S.N., R.N.; Phone Number: 215-898-9275; Email: theresa.scattergood@pennmedicine.upenn.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • Penn Medicine, Smilow Translational Research Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, community dwelling, aged 65 years or older
4. Diagnosed with hypothyroidism of any etiology for at least 6 months, taking 75-200 mcg per day LT4 and a minimum of 1.2 mcg/kg/day with no dose adjustment since the last TSH test.
5. Ability to take oral medication and be willing to adhere to the medication regimen
6. Adherence to lifestyle considerations.

Exclusion Criteria:

1. Hypopituitarism
2. History of thyroid cancer requiring suppression of TSH secretion
3. Current use of liothyronine (LT3), thyroid extracts, Tirosint liquid or capsules, and medications that interfere with thyroid function or thyroid function tests
4. GFR <30 ml/min/1.73 m2 within the prior 12 months
5. Unable to understand and comply with study requirements, as assessed by study staff and the PI, will be excluded.
6. Other conditions which, in the opinion of the investigators, would prevent them from participating in the full duration of the study.
7. Currently taking multikinase or checkpoint inhibitor therapy.
8. Any history of food dye allergy.

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
Active Comparator: Lower TSH Group; Target TSH level of 0.5-2.0 mU/L	Drug: Levothyroxine Sodium; Levothyroxine dose will depend on dose at baseline and randomization group
Experimental: Higher TSH group; Target TSH level of 5.5-7.0 mU/L	Drug: Levothyroxine Sodium; Levothyroxine dose will depend on dose at baseline and randomization group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thyroid-Related Quality of Life Patient-Reported Outcome Quality of Life scale	22 items, scored 0-100, higher scores indicate worse status	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Thyroid-Related Quality of Life Patient-Reported Outcome Hypothyroidism subscale b. ThyPRO "Tiredness" subscale c. Thyroid Symptoms Questionnaire (TSQ)	4 items, scored 0-100, higher scores indicate worse status	6 months
NIH Toolbox Fluid Cognition Composite Score	Adjusted scale score, based around median of 100, higher scores indicated higher function	6 months
Geriatric Depression Scale	30 items, higher scores indicate more depressive symptoms	6 months
Pittsburgh Sleep Quality Index	19 items, range of 0-21, higher scores indicate worse sleep	6 months
Weight	kilograms	6 months
LDL cholesterol	blood test, g/dL	6 months
Satisfaction with randomized status	Participants will be asked if they can guess their randomization status and satisfaction with randomization status	6 months
Beck Anxiety Inventory	Beck Anxiety Inventory, 21 items, range 0-63, higher scores indicate more anxiety	6 months
Serum c-telopeptide (CTX)	Blood test, pg/mL	6 months

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Anne R. Cappola, M.D., Sc.M., University of Pennsylvania

Study record dates

Study Major Dates

• Study Start (Actual): January 31, 2024
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: September 22, 2023
• First Submitted That Met QC Criteria: October 2, 2023
• First Posted (Actual): October 10, 2023

Study Record Updates

• Last Update Posted (Actual): February 19, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Levothyroxine Dosing
• Additional Relevant MeSH Terms: Endocrine System Diseases; Thyroid Diseases; Hypothyroidism; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Peptides, and Proteins; Amino Acids; Amino Acids, Aromatic; Amino Acids, Cyclic; Thyroid Hormones; Thyroxine
• Other Study ID Numbers: 1R01AG081698-01, #853300; R01AG081698 (U.S. NIH Grant/Contract)

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