Clinical trial NCT04288115: Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism
Official title: Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism: a Pilot Randomized, Double-blinded, Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Subclinical Hypothyroidism
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
Collaborators: name: Central Arkansas Veterans Healthcare System
First posted: 2020-02-28
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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).

Eligibility criteria: 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)

Primary outcomes:
measure: Participants' Willingness to Enter the Trial
timeFrame: The time from first consent signed to last consent signed. March 2021 to April 2022.
measure: Recruitment Rate
timeFrame: The time from first consent signed to last consent signed. March 2021 to April 2022. 13 months.
measure: Completion Rate
timeFrame: 6 months
Secondary outcomes:
measure: Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score
timeFrame: Baseline, 6 weeks and 6 months
measure: Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness Score
timeFrame: Baseline, 6 weeks and 6 months
measure: Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) Score at Week 6 and Month 6
timeFrame: 6 weeks and 6 months
measure: Lipid Levels
timeFrame: 6 months
Other outcomes:
Locations:
city: North Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
state: Arkansas
Study officials:
affiliation: Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
name: Spyridoula Maraka, MD MS
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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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.
citation: Ayala IN, Soto Jacome C, Toro-Tobon D, Golembiewski E, Garcia-Bautista A, Hidalgo J, Cordova-Madera S, Al Anbari R, Sohn R J, Singh Ospina N, Maraka S, Joseph M, Brito JP. Appropriateness of Levothyroxine Prescription: A Multicenter Retrospective Study. J Clin Endocrinol Metab. 2024 Jan 18;109(2):e765-e772. doi: 10.1210/clinem/dgad517.
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.
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.
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.