Treatment of Hypothyroid Patients With L-Thyroxine (L-T4) Plus Triiodothyronine Sulfate (T3S). A Phase II, Open-Label, Single Center, Parallel Groups Study on Therapeutic Efficacy and Tolerability

Abstract

Sodium salt of levothyroxine (L-T4) is the treatment of choice of hypothyroidism. Yet, L-T4 monotherapy produces supoptimal 3,5,3'-triiodothyronine (T3)/T4 ratio in serum, as compared to normal subjects, and a minority of hypothyroid individuals on L-T4 complain for an incomplete well-being. Orally administered 3,5,3'-triiodothyronine sulfate (T3S) can be converted to T3 in humans, resulting in steady-state serum T3 concentrations for up to 48 h. In this study (EudraCT number 2010-018663-42), 36 thyroidectomized hypothyroid patients receiving 100 (group A), 125 (group B), or 150 μg (group C) L-T4 were enrolled in a 75 days study in which 25 μg L-T4 were replaced by 40 μg of T3S. A significant, progressive reduction in mean FT4 values was observed, being the largest in the group A and the smallest in group C, while no relevant variations in FT3 and total T3 serum values were observed in the three groups. TSH serum levels increased in all groups, the highest value being observed in group A. Lipid parameters did not show clinically significant changes in all groups. No T3S-related changes in the safety laboratory tests were recorded. No adverse event was judged as related to experimental treatment, and no patient discontinued the treatment. Twelve patients judged the L-T4+T3S treatment better than L-T4 alone, while no patient reported a preference for L-T4 over the combined treatment. In conclusion, the results of this study indicate that a combination of L-T4+T3S in hypothyroid subjects may allow mainteinance of normal levels of serum T3, with restoration of a physiological FT4/FT3 ratio and no appearance of adverse events. Further studies are required to verify whether the LT4+T3S chronic combined treatment of hypothyroidism is able to produce additional benefits over L-T4 monotherapy.

Keywords: 3,5,3′-triiodothyronine sulfate; L-Thyroxine; hypothyroidism; substitutive therapy; thyroid hormone metabolism.

Figure 1

Flow chart of the study. The study plan included a screening visit (Visit 1), in which patients potentially eligible were checked for inclusion and exclusion criteria; Visit 2 was performed within 10 days from Visit 1 to confirm the compliance with the inclusion and the exclusion criteria; if confirmed, the L-T4 therapy schedule was changed to L-T4+T3S. The next visits (max 3 visits: V3a, V3b, and V3c) were performed every 15 days and were dedicated to T3S titration. If during the titration period the patients maintained (or attained) the metabolic control (i.e., hormonal parameters in the accepted range), the T4+T3S dosage remained unchanged until the next follow-up visit (Visit 4, 1 month after), when a T3S dosage change was allowed. A fifth visit (visit 5) was performed after a further month of therapy. If at the end of the titration period (visit 3c) patients did not attained the metabolic control, they were removed from the study. Intermediate visit(s) were arranged in case of adverse events or whenever judged suitable for patient safety by the investigator. A safety follow-up visit (visit 6) was arranged 15 (+ maximum 7) days after visit 5.

Figure 2

Mean (+ SD) changes of free thyroid hormone before (V1) and during L-T4 + T3S therapy in the 34 patients who maintained the same T3S dose throughout the entire study. The various groups are labeled according to the T4/T3S ratio of their treatment regimen: group A = 1.88, group B = 2.5, group C = 3.13.

Figure 3

FT4/FT3 ratio in patients on L-T4 treatment (V1) and on L-T4+T3S (V5). The various groups are labeled according to the T4/T3S ratio of their treatment regimen: group A = 1.88, group B = 2.5, group C = 3.13. The 2 patients from group A and group B, who had to increase the T3S dose to 60 and 80 μg, respectively, are indicated as receiving a T4/T3S ratio = 1.25. The shaded area represents the 95% reference range for the FT4/FT3 ratio in the normal euthyroid population.

Figure 4

Individual concentrations of serum TSH in patients on L-T4 treatment (V1) and on L-T4+T3S (V5). The various groups are labeled according to the T4/T3S ratio of their treatment regimen: group A = 1.88, group B = 2.5, group C = 3.13. The 2 patients from group A and group B, who had to increase the T3S dose to 60 and 80 μg, respectively, are indicated as receiving a T4/T3S ratio = 1.25.