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

Insel Gruppe AG, University Hospital Bern

Status and phase: Completed; Phase 4

Conditions: Subclinical Hypothyroidism; Sarcopenia

Treatments: Drug: Levothyroxin; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT04354896

2011-004554-26 (EudraCT Number)

320030_172676

2012-004160-22 (EudraCT Number)

Details and patient eligibility

About

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.

Full description

Background

Subclinical hypothyroidism (SCH) is common among the elderly population, with an estimated prevalence of 6-15%. It has been associated with multiple adverse outcomes such as cardiovascular diseases and neuropsychological disturbance. Muscular function impairment has also been associated with SCH. However, the association between subclinical hypothyroidism and physical performance in older adults remains unclear and randomized controlled trials are lacking.

Physical performance is an important prognostic indicator for older adults. Prospective studies showed that it is related to hospitalization, institutionalization, cardiovascular disease, disability and mortality. Gait speed is one of the most widely used measures of physical performance in clinical and research settings, with a solid prognostic value.

Aside from overall physical performance, two other dimensions of muscular function can be assessed: muscle function, usually assessed by handgrip strength (predictive validity for decline in cognition, mobility, functional status and mortality for older people), and muscle mass, usually assessed by dual-energy X-absorptiometry). Those three dimension together form the definition of sarcopenia, a relatively new concept which has been gaining visibility in the last years because of its high prevalence and clinical relevance.

Both subclinical hypothyroidism and muscle function impairment are highly prevalent among the older population, and the latter bears a heavy personal, social and economic burden. Therefore, evaluating the potential benefit of levothyroxine therapy on muscle function in this population holds the potential to prevent adverse health-related outcomes and maintain the patients' autonomy and quality of life.

Objectives

To investigate whether levothyroxine therapy in older adults with subclinical hypothyroidism affects sarcopenia measures (mass, strength and physical performance) in a substudy of the TRUST and IEMO trial.

Methods

The existing trial infrastructure (TRUST and IEMO trials, clinicaltrials.gov ID: NCT 01660126) will be utilized to collect information on muscle mass and function from 322 participants with persistent subclinical hypothyroidism randomized to either thyroxine or placebo. Utilized outcomes are specified in the corresponding section.

Enrollment: 322 patients

Sex: All

Ages: 65+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (TRUST):

• 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.]

Inclusion Criteria (IEMO)

• Community-dwelling elderly patients aged ≥80 years with SCH, as above defined

Exclusion Criteria (TRUST and IEMO):

• 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).

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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322 participants in 2 patient groups, including a placebo group

Levothyroxine

Experimental group

Description:

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

Treatment:

Drug: Levothyroxin

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo