The Effect of Thyroid Hormone Therapy on Muscle Mass and Function in Older Adults With Subclinical Hypothyroidism

NCT04354896 | Completed Phase 4 DMC

• 3 other identifiers: 320030_1726762011-004554-262012-004160-22
• Study Type: interventional
• Target: 322
• Locations: 2 countries
• Sites: 5

Brief Summary

Subclinical hypothyroidism (SCH) is common among the elderly population and has been associated with neuromuscular impairment. Muscular symptoms such as weakness, myalgia and cramps are more often reported by SCH patients compared to euthyroid controls. Sarcopenia is the age-related loss of muscular mass and function and its assessment includes three dimensions (muscle quantity, muscle strength and physical performance). To date, evidence is lacking about the effect of thyroid hormone replacement on skeletal muscle impairment in SCH patients. The aim of the study is therefore to evaluate the impact of levothyroxine therapy on sarcopenia measures in SCH. This is a nested substudy within two large international multicenter randomized controlled trial of elderly participants with SCH (TRUST Study, clinicaltrials.gov ID NCT 01660126; and IEMO Study, Netherland Trial Register ID NTR3851). Those two trials shared a very similar study design. The cohorts will therefore be analyzed as a single study population.

Conditions

Subclinical Hypothyroidism; Sarcopenia

Keywords

Physical performance; muscle mass; muscle function

Outcome Measures

Primary Outcomes (1)

• Physical performance

  Gait speed (3-meter and 6-meter walk test) \[m/s\]

  Final visit (12 to 42 months after baseline visit)

Secondary Outcomes (3)

• Muscle mass

  Baseline, 1-year follow up and/or 2-year follow-up (yearly change)

• Muscle strength

  Baseline, 1-year follow-up

• Sarcopenia

  Final visit (12 to 42 months after baseline visit)

Study Arms (2)

Levothyroxine

EXPERIMENTAL

The intervention will start with Levothyroxine 50 mcg daily with regular blinded dosis titration.

Drug: Levothyroxin

Placebo

PLACEBO COMPARATOR

Pharmaceutical composition of placebo (100 mg): Lactose monohydrate 66 mg, Maize starch 25 mg, Gelatin 5 mg, Croscarmellose sodium 3.5 mg, Magnesium stearate (vegetable source) 0.5 mg.

Drug: Placebo

Interventions

Levothyroxin DRUG

The intervention will start with Levothyroxine 50 mcg daily (reduced to 25 mcg in subjects \<50 kg of body weight or if known coronary heart disease - previous myocardial infarction or symptoms of angina pectoris) vs. matching placebo; at 3 months, if the serum TSH level is \<0.4 mU/L, dose will be reduced by 25 mcg; TSH 0.4 to 4.6 mU/L, no change to dose; TSH ≥4.6 mU/L, additional 25 mcg. The process will be repeated at 12 months, then annually; mock titration will be performed in the placebo group. The maximum possible dose of Levothyroxine which will be prescribed is 150 mcg (after 4 increments of 25 mcg at 3 months, 1, 2, 3 years; from the starting dose of 50 mcg).

Levothyroxine

Placebo DRUG

Control patients will obtain a placebo pill of the same characteristics as the intervention drug, and mock titration will be carried out identically to the intervention drug.

Placebo

Eligibility Criteria

• Age: 65 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Community-dwelling elderly patients aged ≥65 years with subclinical hypothyroidism (SCH).
• \[SCH is defined as elevated TSH levels (4.6 to 19.9 mU/L) and free thyroxine (fT4) in reference range measured on a minimum of two occasions at least 3 months apart.\]
• \- Community-dwelling elderly patients aged ≥80 years with SCH, as above defined

You may not qualify if:

• Currently on Levothyroxine or antithyroid drugs, amiodarone or lithium.
• Recent thyroid surgery or radio-iodine (within 12 months).
• Grade IV NYHA heart failure.
• Prior clinical diagnosis of dementia.
• Recent hospitalisation for major illness or elective surgery (within 4 weeks).
• Recent acute coronary syndrome, including myocardial infarction or unstable angina (within 4 weeks).
• Terminal illness.
• Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
• Individuals participating in ongoing RCTs of therapeutic interventions (including CTIMPs)
• Individuals planning to move out of the region in which the trial is being conducted within the next 2 years (proposed minimum follow-up period).

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• University of Lausanne Hospitals: collaborator
• Leiden University Medical Center: collaborator

Study Sites (5)

Department of Gerontology and Geriatrics, Leiden University Medical Center

Leiden, Netherlands

Location

Department of Public Health and Primary Care, Leiden University Medical Center

Leiden, Netherlands

Location

Institute for Evidence-Based Medicine in Old Age

Leiden, Netherlands

Location

Department of General Internal Medicine

Lausanne, Canton of Vaud, 1011, Switzerland

Location

Clinic for General Internal Medicine, Bern University Hospital Bern

Bern, 3010, Switzerland

Location

Related Publications (4)

• 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.

  PMID: 28402245 BACKGROUND

• Stott DJ, Gussekloo J, Kearney PM, Rodondi N, Westendorp RG, Mooijaart S, Kean S, Quinn TJ, Sattar N, Hendry K, Du Puy R, Den Elzen WP, Poortvliet RK, Smit JW, Jukema JW, Dekkers OM, Blum M, Collet TH, McCarthy V, Hurley C, Byrne S, Browne J, Watt T, Bauer D, Ford I. Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST). BMC Endocr Disord. 2017 Feb 3;17(1):6. doi: 10.1186/s12902-017-0156-8.

  PMID: 28158982 BACKGROUND

• Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RGJ, den Elzen WPJ, Postmus I, Poortvliet RKE, van Heemst D, van Munster BC, Peeters RP, Ford I, Kean S, Messow CM, Blum MR, Collet TH, Watt T, Dekkers OM, Jukema JW, Smit JWA, Langhorne P, Gussekloo J. Association Between Levothyroxine Treatment and Thyroid-Related Symptoms Among Adults Aged 80 Years and Older With Subclinical Hypothyroidism. JAMA. 2019 Nov 26;322(20):1977-1986. doi: 10.1001/jama.2019.17274.

  PMID: 31664429 BACKGROUND

• Netzer S, Chocano-Bedoya P, Feller M, Janett-Pellegri C, Wildisen L, Buchi AE, Moutzouri E, Gonzalez Rodriguez E, Collet TH, Poortvliet RKE, Mc Carthy VJC, Aeberli D, Aujesky D, Westendorp R, Quinn TJ, Gussekloo J, Kearney PM, Mooijaart S, Bauer DC, Rodondi N. The effect of thyroid hormone therapy on muscle function, strength and mass in older adults with subclinical hypothyroidism-an ancillary study within two randomized placebo controlled trials. Age Ageing. 2023 Jan 8;52(1):afac326. doi: 10.1093/ageing/afac326.

  PMID: 36721961 DERIVED

MeSH Terms

Conditions

Sarcopenia

Interventions

Thyroxine

Condition Hierarchy (Ancestors)

Muscular Atrophy; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Atrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thyroid Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Nicolas Rodondi, MD MAS

  BIHAM UniBern

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 8, 2020
• First Posted: April 21, 2020
• Study Start: May 1, 2014
• Primary Completion: May 4, 2018
• Study Completion: May 4, 2018
• Last Updated: May 18, 2023

Record last verified: 2023-05

Locations

NL (3); CH (2)