Abstract
Hypothyroidism is a common condition with a wide spectrum of etiologies and clinical manifestations. While the majority of patients affected by hypothyroidism respond well to levothyroxine, some patients do not and complain of symptoms despite adequate replacement. There is evidence in experimental models of hypothyroidism that levothyroxine alone may not be able to deliver an adequate amount of T3 to all the tissues targeted by the hormonal action, while liothyronine/levothyroxine combination therapy can. The results of clinical studies directed to assess the effectiveness of liothyronine/levothyroxine combination therapy on the amelioration of hypothyroid symptoms have been disappointing. Most of the trials have been short and underpowered, with several shortcomings in the study design. There is consensus that an adequately powered clinical trial should be developed to prove or disprove the efficacy and effectiveness of therapies other than LT4 alone for the treatment of hypothyroidism, and to assess which group of patients would benefit from them. Here we present some considerations on the technical aspects and necessary tradeoffs in designing such a study with a particular focus on study population selection, choice of endpoints, and study drugs formulation and regimen.
Highlights
The majority of the patients affected by hypothyroidism are successfully treated with levothyroxine (LT4), which is considered by U.S professional organizations to be the standard of care for this condition [1, 2]
Obvious advantages of LT4 thyroid hormone replacement therapy include well-known pharmacokinetics characteristics which allow for daily administration, its safety profile, and the wide array of dose strengths which allow for precise titration
The clinical significance of these changes in thyroid hormone is not clear, but it may reflect a state of relative imbalance in the thyroid hormone axis homeostasis, which in turn could cause the persistence of hypothyroid symptoms in some individuals
Summary
The majority of the patients affected by hypothyroidism are successfully treated with levothyroxine (LT4), which is considered by U.S professional organizations to be the standard of care for this condition [1, 2]. Several clinical trials (Table 1) have been conducted with various treatment schemes, duration, and endpoints [9,10,11,12,13,14,15,16, 18,19,20,21,22,23,24] The results of these studies have been inconsistent, and in the aggregate LT3:LT4 combination therapy or DTE [25] have not shown superiority to LT4 in relieving symptoms of hypothyroidism. Study design or treatment scheme decisions based on extraneous constrain would inevitably result in an inadequate intervention The goal of this manuscript is to discuss these variables in the context to provide the rationale to design future LT3:LT4 combination therapy clinical trials. This is certainly a valid question, but Frontiers in Endocrinology | www.frontiersin.org
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