Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism

Subclinical Hypothyroidism Clinical Trial

Official title:

Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism: a Pilot Randomized, Double-blinded, Placebo-controlled Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04288115
• Other study ID #: PPO 20-056
• Secondary ID: 1521422
• Status: Completed
• Phase: Phase 4
• Start date: March 24, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: November 2023
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators propose the following hypothesis: discontinuation of levothyroxine (LT4) for veterans with subclinical hypothyroidism (SCH) will be feasible, acceptable, and safe and will not negatively affect their Quality of Life (QoL). The investigators aim to evaluate the feasibility of LT4 discontinuation among veterans with SCH and determine the changes in QoL measures, lipids, and adverse events.

Description:

This is a pilot, randomized, double-blind, placebo-controlled trial.

Methodology:

The investigators will conduct a double-blind, placebo-controlled clinical trial where eligible veterans diagnosed with SCH and on LT4 will be 1:1 randomized to either continue LT4 or change to placebo. The primary outcome is intervention feasibility (willingness to enter the trial, recruitment rate, and completion rate). Secondary outcomes are: 1) changes in QoL measures (Hypothyroid Symptom [HSS] and Tiredness scale scores of the Thyroid-Specific Patient-Related Outcome Measure [ThyPRO], EuroQoL 5-Dimension Self-Report Questionnaire) measured at baseline, 6-8 weeks and 6 months and 2) changes in lipids assessed at baseline and 6 months, and 3) incidence of adverse events (overt hypothyroidism, hyperthyroidism, atrial fibrillation, fractures, acute myocardial infarction, stroke, acute coronary syndrome, heart failure, mortality).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: December 31, 2022
• Est. primary completion date: October 7, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Veterans

• diagnosis of SCH

Exclusion Criteria:

• thyroid-stimulating hormone (TSH) > 10 milli-international units per liter (mlU/L) (at any point)

• Levothyroxine (LT4) dose more than 75 mcg daily

• use of antithyroid medications, amiodarone, tyrosine kinase inhibitors or lithium

• history of thyroidectomy or radioactive iodine therapy

• LT4 suppressive therapy for thyroid cancer, goiter, or inflammation

• pregnancy or plans for pregnancy in the next 6 months

• an unstable medical condition that would jeopardize safety or interfere with study participation

• severe hypothyroidism-related symptoms

• strong family history of hypothyroidism

• severe dyslipidemia

• hospitalization for major illness within the previous 4 weeks

• acute coronary artery syndrome, acute myocarditis, or pancarditis with the previous 12 months

• grade IV New York Heart Association heart failure

• receiving services from hospice

• lack of decision-making capacity

• terminal medical condition for which life expectancy would be less than 6 months

• not willing to stop LT4

• self-reported non-adherence to LT4 therapy

• abnormal TSH at time of screening for participation (assessed during Baseline Visit)

Related Conditions & MeSH terms

• Hypothyroidism
• Subclinical Hypothyroidism

Intervention

Drug:
• Levothyroxine
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.

Other:
• Placebo
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.

Locations

Country	Name	City	State
United States	Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR	North Little Rock	Arkansas

Sponsors (2)

Lead Sponsor	Collaborator
VA Office of Research and Development	Central Arkansas Veterans Healthcare System

Country where clinical trial is conducted

United States, 

References & Publications (8)

Ayala IN, Soto Jacome C, Toro-Tobon D, Golembiewski E, Garcia Bautista AE, Hidalgo J, Cordova-Madera S, Al Anbari R, Sohn JR, Singh Ospina N, Maraka S, Joseph M, Brito JP. Appropriateness of Levothyroxine Prescription: A Multicenter Retrospective Study. J Clin Endocrinol Metab. 2023 Sep 1:dgad517. doi: 10.1210/clinem/dgad517. Online ahead of print. — View Citation

Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, Abdulazeem H, Aertgeerts B, Beecher D, Brito JP, Farhoumand PD, Singh Ospina N, Rodondi N, van Driel M, Wallace E, Snel M, Okwen PM, Siemieniuk R, Vandvik PO, Kuijpers T, Vermandere M. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019 May 14;365:l2006. doi: 10.1136/bmj.l2006. — View Citation

Brito JP, Ross JS, El Kawkgi OM, Maraka S, Deng Y, Shah ND, Lipska KJ. Levothyroxine Use in the United States, 2008-2018. JAMA Intern Med. 2021 Oct 1;181(10):1402-1405. doi: 10.1001/jamainternmed.2021.2686. — View Citation

Burgos N, Toloza FJK, Singh Ospina NM, Brito JP, Salloum RG, Hassett LC, Maraka S. Clinical Outcomes After Discontinuation of Thyroid Hormone Replacement: A Systematic Review and Meta-Analysis. Thyroid. 2021 May;31(5):740-751. doi: 10.1089/thy.2020.0679. Epub 2020 Dec 29. — View Citation

Feller M, Snel M, Moutzouri E, Bauer DC, de Montmollin M, Aujesky D, Ford I, Gussekloo J, Kearney PM, Mooijaart S, Quinn T, Stott D, Westendorp R, Rodondi N, Dekkers OM. Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis. JAMA. 2018 Oct 2;320(13):1349-1359. doi: 10.1001/jama.2018.13770. — View Citation

Ospina NS, Salloum RG, Maraka S, Brito JP. De-implementing low-value care in endocrinology. Endocrine. 2021 Aug;73(2):292-300. doi: 10.1007/s12020-021-02732-y. Epub 2021 May 11. — View Citation

Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, Sattar N, Aubert CE, Aujesky D, Bauer DC, Baumgartner C, Blum MR, Browne JP, Byrne S, Collet TH, Dekkers OM, den Elzen WPJ, Du Puy RS, Ellis G, Feller M, Floriani C, Hendry K, Hurley C, Jukema JW, Kean S, Kelly M, Krebs D, Langhorne P, McCarthy G, McCarthy V, McConnachie A, McDade M, Messow M, O'Flynn A, O'Riordan D, Poortvliet RKE, Quinn TJ, Russell A, Sinnott C, Smit JWA, Van Dorland HA, Walsh KA, Walsh EK, Watt T, Wilson R, Gussekloo J; TRUST Study Group. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. doi: 10.1056/NEJMoa1603825. Epub 2017 Apr 3. — View Citation

Toloza FJK, El Kawkgi OM, Spencer HJ, Mathews SE, Garcia A, Gamboa A, Mirza N, Mohan S, Vallejo S, Bogojevic M, Rodriguez-Gutierrez R, Singh Ospina NM, Brito JP, Maraka S. Determinants for Thyroid Hormone Replacement Therapy in Subclinical Hypothyroidism: A Multicenter Electronic Health Records-Based Study. Thyroid. 2023 Sep;33(9):1045-1054. doi: 10.1089/thy.2023.0062. Epub 2023 Jun 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participants' Willingness to Enter the Trial	Percent of eligible participants approached who consented to participate during the recruitment phase.	The time from first consent signed to last consent signed. March 2021 to April 2022.
Primary	Recruitment Rate	The number of enrolled (consented) participants divided by the length of the recruitment period.	The time from first consent signed to last consent signed. March 2021 to April 2022. 13 months.
Primary	Completion Rate	Percentage of randomized participants who completed the trial.	6 months
Secondary	Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score	The Hypothyroid Symptoms score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more symptoms.	Baseline, 6 weeks and 6 months
Secondary	Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score	The Tiredness score from the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire is assessed on a scale from 0 to 100, with higher scores indicating more tiredness.	Baseline, 6 weeks and 6 months
Secondary	Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6	The EuroQoL [EQ] Group 5-Dimension Self-Report Questionnaire (EQ-5D) scores include the EQ-5D descriptive index, on a scale from -0.59 to 1.00. Higher scores indicate better quality of life. The EQ-5D scores include the score on the EQ visual-analogue scale (EQ-5D VAS), on a scale from 0 to 100. Higher scores indicate better quality of life.	6 weeks and 6 months
Secondary	Lipid Levels	Differences in mean 6-month lipid levels after adjusting for gender and baseline lipid level.	6 months