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.

Grant Number: 5R01DK140455-02
NIH Institute/Center: NIH
Principal Investigator: FRANCESCO CELI