New Approaches for the treatment of Hypothyroidism

Project Summary This submission is in response to PAS-23-086, Small R01s for Clinical Trials Targeting Diseases within the Mission of NIDDK. Hypothyroidism is a common condition associated with excess of cardiovascular risk and poor quality of life which are not completely abrogated by treatment with levothyroxine (synthetic T4, LT4), potentially

because of the inability to compensate for the loss of T3 secreted by the thyroid gland. Experimental data in animal models indicate that only combination LT4 and liothyronine (synthetic T3, LT3) can restore normal concentrations of thyroid hormones across the tissues target of the hormonal action. Clinical trials based on

LT4/LT3 combination therapy and desiccated thyroid extracts (containing T3) have provided conflicting data, but the plurality of the results indicates a preference toward T3-containing therapies when compared to LT4 alone. Conversely, the short half-life of T3 poses concern of cardiovascular toxicity due to fluctuating levels of

T3, particularly when LT3 is prescribed in single dose. No study has systematically assessed the optimal dose and frequency of LT3 administration in LT4/LT3 combination therapy. There is an unmet need to define a safe, effective, and feasible regimen to be applied in large trials aimed at assessing LT4/LT3 therapy efficacy and

safety. We have conducted clinical studies aimed at characterizing the pharmacokinetics and pharmacodynamics of LT3 and, more recently, we completed a R21-sponsored LT4/LT3 combination therapy clinical trial in patients undergoing total thyroidectomy. The data suggest that LT4/LT3 combination therapy is

effective in normalizing thyroid hormone levels and in preventing the rise in serum cholesterol and weight when compared to LT4 alone. Moreover, our results from a prior study appear to negate a clinical role of rapid T3 action, supporting the use of LT3 in single administration. These original findings serve as foundation for the

current proposal. Hypothesis: A once daily administration of LT4/LT3 combination therapy will be (i) effective yet safe, (ii) comparable to a twice daily LT4/LT3 administration regimen, and (iii) superior to LT4 therapy in improving clinically relevant indices of thyroid hormone action. To test this hypothesis, we propose a randomized, three-arm, double-blind, controlled, escalating

dose parallel pilot study in which 90 patients with hypothyroidism (30 each group) will be randomized to six months of treatment with LT4, LT4/LT3 with LT3 once daily, or LT4/LT3 with LT3 twice daily. This novel and rigorous study based on our original observations will fill the knowledge gap of effects

and dosing of LT4/LT3 combination therapy, laying the foundation for large multicenter trial(s) able to demonstrate the effectiveness (or lack thereof) of LT4/LT3 combination therapy, fulfilling the aims of PAS-23- 086.