PROJECT SUMMARY Hypothyroidism is a common disorder that requires lifelong treatment with thyroid hormone replacement. Levothyroxine (LT4), a sodium salt of the thyroid hormone thyroxine (T4), is the recommended medication for thyroid hormone replacement, but it fails to replicate normal thyroid physiology, which includes production of both the thyroid hormones T4 and triiodothyronine (T3). The clinical implications of non-physiologic thyroid hormone replacement are not clear. A substantial minority of patients with hypothyroidism have residual symptoms of hypothyroidism despite receiving recommended doses of LT4. An adequately powered, randomized, double-blind, placebo-controlled clinical trial of combination therapy with LT4 and T3 replacement (LT3) is required to provide high-quality evidence to guide management of the millions of patients treated for hypothyroidism. The goal of this proposal is to generate pilot and feasibility data required to design and lead this definitive trial. The investigators involved in this protocol have experience in LT3 administration in both clinical and research settings, and they have led the US-based and international guidelines that provide a roadmap for the proposed RCT design. Data required for the design of a clinical trial of combination therapy include refinement of the study population, dosing strategy for LT4 and LT3, primary and secondary outcome selection, and evaluation of statistical power. We are targeting the study population to those most likely to benefit: individuals requiring LT4 doses of at least 1.2 mcg/kg/day who have residual symptoms. We will include important subgroups, stratifying randomization by underlying etiology of hypothyroidism (autoimmune vs. thyroid absence) and analysis by the severity of symptoms and the presence of a genetic polymorphism that affects metabolism of T4 to T3. We will refine the dosing strategy to ensure equivalence of thyroid stimulating hormone (TSH) levels between LT4/LT3 and LT4/placebo groups using a novel, low-dose LT3 preparation. We will refine primary and secondary outcome selection, symptom and safety monitoring, and obtain estimates of efficacy for sample size calculations of the large RCT. The proposed aims will provide essential data on feasibility, preliminary efficacy, and study conduct to inform a fully powered clinical trial of combination therapy of LT4/LT3 in patients with hypothyroidism. This definitive clinical trial would resolve the outstanding question of whether a “more physiologic” thyroid hormone replacement regimen that includes both LT4 and LT3 would benefit patients with residual symptoms taking current standard-of-care therapy with LT4 alone.
