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Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism

Primary Purpose

Subclinical Hypothyroidism

Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Levothyroxine
Placebo
Sponsored by
VA Office of Research and Development
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Subclinical Hypothyroidism

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Veterans
  • diagnosis of SCH between January 1, 2009 and December 31, 2019, at the Central Arkansas Veterans Healthcare System (CAVHS)

Exclusion Criteria:

  • TSH > 10 mlU/L (at any point)
  • 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)

Sites / Locations

  • Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Levothyroxine group ("sham discontinuation")

Placebo group ("real discontinuation")

Arm Description

Continue the current dose of levothyroxine. The brand of levothyroxine to be used in this study will be Synthroid tablets of 25 mcg, 50 mcg, and 75 mcg (AbbVie Inc).

Stop the current dose of levothyroxine and take study placebo

Outcomes

Primary Outcome Measures

Participants' willingness to enter the trial
Percent of eligible participants approached who consented to participate during the recruitment phase
Recruitment rate
The number of randomized participants divided by the length of the recruitment period
Completion rate
Percent of randomized participants who completed the trial

Secondary Outcome Measures

Change in Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Change in Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness score
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Change in Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) score
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Change in lipid levels
Changes in score from baseline to 6 months. Positive change/difference is a worse outcome.

Full Information

First Posted
February 14, 2020
Last Updated
February 15, 2023
Sponsor
VA Office of Research and Development
Collaborators
Central Arkansas Veterans Healthcare System
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1. Study Identification

Unique Protocol Identification Number
NCT04288115
Brief Title
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

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
March 2, 2021 (Actual)
Primary Completion Date
October 7, 2022 (Actual)
Study Completion Date
December 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
Collaborators
Central Arkansas Veterans Healthcare System

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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 1) evaluate the feasibility of LT4 discontinuation among veterans with SCH and determine the changes in QoL measures, lipids, and adverse events, and 2) assess the acceptability of LT4 discontinuation among veterans with SCH and LT4 prescribing clinicians.
Detailed Description
This is a pilot, randomized, double-blind, placebo-controlled trial. Semi-structured interviews, from randomized participants and LT4 prescribers, will be completed at the end of the 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 and Tiredness scale scores of the 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). The investigators will assess the acceptability of LT4 discontinuation through semi-structured qualitative interviews with participants and LT4 prescribers at the completion of the clinical trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Subclinical Hypothyroidism

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Levothyroxine group ("sham discontinuation")
Arm Type
Active Comparator
Arm Description
Continue the current dose of levothyroxine. The brand of levothyroxine to be used in this study will be Synthroid tablets of 25 mcg, 50 mcg, and 75 mcg (AbbVie Inc).
Arm Title
Placebo group ("real discontinuation")
Arm Type
Placebo Comparator
Arm Description
Stop the current dose of levothyroxine and take study placebo
Intervention Type
Drug
Intervention Name(s)
Levothyroxine
Other Intervention Name(s)
Synthroid
Intervention Description
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Participants will be instructed to start the study medication the day after randomization. The study medication will be taken orally once a day.
Primary Outcome Measure Information:
Title
Participants' willingness to enter the trial
Description
Percent of eligible participants approached who consented to participate during the recruitment phase
Time Frame
from the date that recruitment opened to the date of the last randomization, an average of 6 months
Title
Recruitment rate
Description
The number of randomized participants divided by the length of the recruitment period
Time Frame
from the date that recruitment opened to the date of the last randomization, an average of 6 months
Title
Completion rate
Description
Percent of randomized participants who completed the trial
Time Frame
through study completion, an average of 6 months
Secondary Outcome Measure Information:
Title
Change in Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Hypothyroid Symptoms Score
Description
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Time Frame
Baseline, 6-8 weeks and 6 months.
Title
Change in Thyroid-specific Quality of Life Patient-Reported Outcome (ThyPRO) - Tiredness score
Description
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Time Frame
Baseline, 6-8 weeks and 6 months.
Title
Change in Euro Quality of Life 5-Dimension Self-Report Questionnaire (EQ-5D) score
Description
Changes in score from baseline to 6-8 weeks, and from baseline to 6 months. Negative change/difference is a worse outcome.
Time Frame
Baseline, 6-8 weeks and 6 months.
Title
Change in lipid levels
Description
Changes in score from baseline to 6 months. Positive change/difference is a worse outcome.
Time Frame
Baseline and 6 months.
Other Pre-specified Outcome Measures:
Title
Acceptability of intervention: qualitative interview
Description
qualitative interview to provide feedback on experiences
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
89 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Veterans diagnosis of SCH between January 1, 2009 and December 31, 2019, at the Central Arkansas Veterans Healthcare System (CAVHS) Exclusion Criteria: TSH > 10 mlU/L (at any point) 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Spyridoula Maraka, MD MS
Organizational Affiliation
Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
Official's Role
Principal Investigator
Facility Information:
Facility Name
Central Arkansas Veterans Healthcare System Eugene J. Towbin Healthcare Center, Little Rock, AR
City
North Little Rock
State/Province
Arkansas
ZIP/Postal Code
72114-1706
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34379311
Citation
Edwards MK, Iniguez-Ariza NM, Singh Ospina N, Lincango-Naranjo E, Maraka S, Brito JP. Inappropriate use of thyroid ultrasound: a systematic review and meta-analysis. Endocrine. 2021 Nov;74(2):263-269. doi: 10.1007/s12020-021-02820-z. Epub 2021 Aug 11.
Results Reference
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PubMed Identifier
33483783
Citation
Kotsougiani-Fischer D, Sieber L, Fischer S, Hirche C, Maraka S, Kneser U. Safety of a Modified Lipoabdominoplasty Technique for Donor-Site Closure in Abdominal-Based Free Flap Breast Reconstruction. Aesthetic Plast Surg. 2021 Aug;45(4):1431-1440. doi: 10.1007/s00266-020-02117-y. Epub 2021 Jan 22.
Results Reference
background
PubMed Identifier
34074037
Citation
Vadhiraj VV, Simpkin A, O'Connell J, Singh Ospina N, Maraka S, O'Keeffe DT. Ultrasound Image Classification of Thyroid Nodules Using Machine Learning Techniques. Medicina (Kaunas). 2021 May 24;57(6):527. doi: 10.3390/medicina57060527.
Results Reference
background
PubMed Identifier
34152370
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.
Results Reference
background
Citation
Albashaireh A., Maraka S. Iron Deficiency Is Associated with Maternal Hypothyroxinemia in the Third Trimester of Pregnancy. Clinical Thyroidology. 2021 Dec 1; doi.org/10.1089/ct.2021;33.526-528.
Results Reference
background
PubMed Identifier
34956101
Citation
Ding Z, Liu Y, Maraka S, Abdelouahab N, Huang HF, Fraser WD, Fan J. Pregnancy and Neonatal Outcomes With Levothyroxine Treatment in Women With Subclinical Hypothyroidism Based on New Diagnostic Criteria: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2021 Dec 10;12:797423. doi: 10.3389/fendo.2021.797423. eCollection 2021.
Results Reference
background
PubMed Identifier
33201541
Citation
Siegwart LC, Sieber L, Fischer S, Maraka S, Kneser U, Kotsougiani-Fischer D. Influence of closed incision negative-pressure therapy on abdominal donor-site morbidity in microsurgical breast reconstruction. Microsurgery. 2022 Jan;42(1):32-39. doi: 10.1002/micr.30683. Epub 2020 Nov 17.
Results Reference
background
Citation
Albashaireh A, Maraka S. Thyroid Function Classification in Early Pregnancy Varies Considerably Across Repeated Testing Within an Interval of a Few Weeks. Clinical Thyroidology. 2022 Apr 14; 34(4):https://doi.org/10.1089/ct.2022;34.153-156.
Results Reference
background
PubMed Identifier
35521676
Citation
Burgos N, Zhao J, Brito JP, Hoang JK, Pitoia F, Maraka S, Castro MR, Lee JH, Singh Ospina N. Clinician Agreement on the Classification of Thyroid Nodules Ultrasound Features: A Survey of 2 Endocrine Societies. J Clin Endocrinol Metab. 2022 Jul 14;107(8):e3288-e3294. doi: 10.1210/clinem/dgac279.
Results Reference
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PubMed Identifier
35596568
Citation
Bliddal S, Derakhshan A, Xiao Y, Chen LM, Mannisto T, Ashoor G, Tao F, Brown SJ, Vafeiadi M, Itoh S, Grineva EN, Taylor P, Ghafoor F, Vaidya B, Hattersley A, Mosso L, Oken E, Kishi R, Alexander EK, Maraka S, Huang K, Chaker L, Bassols J, Pirzada A, Lopez-Bermejo A, Boucai L, Peeters RP, Pearce EN, Nelson SM, Chatzi L, Vrijkotte TG, Popova PV, Walsh JP, Nicolaides KH, Suvanto E, Lu X, Pop VJM, Forman JL, Korevaar TIM, Feldt-Rasmussen U. Association of Thyroid Peroxidase Antibodies and Thyroglobulin Antibodies with Thyroid Function in Pregnancy: An Individual Participant Data Meta-Analysis. Thyroid. 2022 Jul;32(7):828-840. doi: 10.1089/thy.2022.0083.
Results Reference
background
Citation
ElSheikh R, Maraka S. The Incidence of Clinically Relevant Thyroid Cancers Remains Stable. Clinical Thyroidology. 2022 Jan 4; 34(1):26-28.
Results Reference
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Discontinuation of Levothyroxine Therapy for Patients With Subclinical Hypothyroidism

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