Study protocol; Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial (TRUST)

Abstract

BackgroundSubclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH.MethodsParticipants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p = 0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients.Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture.DiscussionThis large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition.Trial registrationClinicaltrials.gov NCT01660126; registered 8th June 2012.Electronic supplementary materialThe online version of this article (doi:10.1186/s12902-017-0156-8) contains supplementary material, which is available to authorized users.

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism

“…The primary and secondary outcomes at 12 months were also analyzed in prespecified subgroups according to sex and baseline thyrotropin level. 11 Analyses were repeated in the perprotocol population, which included participants who continued to take the trial regimen per the trial protocol.…”

“…The trial protocol, which was published previously 11 and is available with the full text of this article at NEJM.org, was approved by the relevant ethics committees and regulatory authorities in all the countries involved in the trial. Participants provided written informed consent.…”

The effect of levothyroxine treatment in individuals with subclinical hypothyroidism on surrogate markers of atherosclerosis: a meta-analysis of randomized controlled trials

“…We believe the difference is mostly due to the significant weight of the recent study performed by Blum et al in 2018, which concluded no significant improvement of CIMT [3]. Nevertheless, the Blum study was part of the TRUST trial, which was limited to older patients (mean age was 74.4 years) [6]. In addition, in 2017, Aziz et al performed a metaanalysis that was not limited RCTs and concluded that thyroxine treatment decreased CIMT and improved lipid profile in individuals with SCH [8].…”

“…65 years and older) with SCH and concluded there was no impact on CIMT after treatment [3]. This RCT was nested within the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism (TRUST) trial [6]. Despite being the largest multinational RCT examining levothyroxine treatment in the elderly population with SCH, the TRUST trial was not powered enough to detect a difference in the clinical cardiovascular outcomes [3].…”

Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism

“…Justification for these power calculations is provided in the trial protocol. 11 The methods of analysis of the continuous efficacy outcomes involving measurements at baseline and follow-up were analyzed at each time point for the comparison of the two trial groups, with adjustment for stratification variables (country, sex, and starting dose of levothyroxine) and baseline levels of the same variable with the use of multivariate linear regression (see the Supplementary Appendix). The efficacy and safety analyses were carried out in a modified intention-to-treat population, which included T h e ne w e ngl a nd jou r na l o f m e dicine participants with data on the outcome of interest.…”