Randomized Trial of Levothyroxine Sodium + Liothyronine Sodium versus Levothyroxine for TSH Control in Advanced Thyroid Carcinoma Patients on Tyrosine Kinase Inhibitors

The primary objective is to evaluate the efficacy of combined levothyroxine (LT4) plus liothyronine (LT3) therapy versus LT4 monotherapy in controlling TSH in patients with advanced thyroid carcinoma receiving tyrosine kinase inhibitors.

Secondary objectives include:

• Evaluation of longitudinal trends in free T3 (FT3) and free T4 (FT4) over 24 weeks following initiation of TKI therapy.
• Comparison of health‑related quality of life between the combination therapy and monotherapy groups during TKI treatment.
• Investigation of the relationship between changes in serum thyroid hormone levels and low‑density lipoprotein (LDL) cholesterol as a peripheral thyroid hormone metabolism marker.
• Investigation of the relationship between hormone level changes and the Thr92Ala polymorphism of the DIO2 gene.
• Assessment of safety with emphasis on cardiovascular and neuropsychiatric events associated with thyroid hormone excess.
• Assessment of the stability of TSH control in the two treatment arms.

The trial enrolled adult patients, both male and female, aged 18 to < 80 years, diagnosed with advanced thyroid carcinoma and post‑thyroidectomy hypothyroidism, receiving levothyroxine (LT4) therapy and eligible for systemic tyrosine‑kinase inhibitor treatment. Participants were required to have circulating TSH levels between 0.1 and 0.5 mIU/L and an ECOG performance status of ≤2 without recent deterioration. The sponsor did not provide the total number of participants. Selection was based on the specified diagnostic and therapeutic criteria; no specific dietary, physical‑activity, or habit restrictions were stipulated in the available information.

In this prospective, multicenter, phase IV trial, participants aged 18–79 years with locally advanced or metastatic advanced thyroid carcinoma and postoperative hypothyroidism are randomized in a 1:1 ratio to receive either levothyroxine (LT4) monotherapy (tablet or oral solution) or combined levothyroxine plus liothyronine (LT4 + LT3) therapy (oral solution or drops) after initiation of tyrosine‑kinase inhibitor treatment. The study employs a parallel‑group, controlled design with allocation concealed; investigators and participants remain blinded to the assigned regimen. The overall study period spans approximately two years, with individual participation lasting 24 weeks from the first dose. After an initial screening visit to confirm eligibility and baseline laboratory values, eligible subjects undergo a randomization visit (week 0) at which study medication is dispensed. Subsequent study visits occur at weeks 4, 12 and 24 for assessment of serum thyroid hormones, lipid profile, quality‑of‑life questionnaires, and safety monitoring; an end‑of‑study visit at week 24 concludes the intervention phase. Participants are required to remain on the assigned regimen without dose adjustments of LT4 or LT3; protocol‑defined criteria such as persistent TSH < 0.1 mIU/L, TSH > 0.5 mIU/L despite adherence, or emergence of serious adverse events may trigger early discontinuation. Primary efficacy is evaluated by the proportion of subjects maintaining TSH within the target range (0.1–0.5 mIU/L) throughout the 24‑week period, with secondary endpoints including changes in FT3, FT4, LDL cholesterol, quality‑of‑life scores, and pharmacogenomic correlations.

Levothyroxine is administered as a 400 µg dose in a tablet formulation (EUTIROX 100 µg tablets) and is taken orally.

The comparator oral solution (LEVOTIRSOL 100 µg in a single‑dose container) also provides a 400 µg dose of levothyroxine sodium and is administered orally.

Liothyronine sodium is supplied in an oral solution at a concentration of 15 µg/mL (Liotir 15 µg/mL solution) and is dosed at 40 µg per administration.

An oral solution of liothyronine sodium at 20 µg/mL (Liotir 20 µg/mL solution) is provided for a 40 µg dose.

Liothyronine sodium is also available as oral drops in a 20 µg/mL solution (Liotir 20 µg/mL oral drops) for a 40 µg dose.

A 5 µg/mL oral solution of liothyronine sodium (Liotir 5 µg/mL solution) is used to deliver a 40 µg dose.

Finally, a 10 µg/mL oral solution of liothyronine sodium (Liotir 10 µg/mL solution) provides a 40 µg dose, administered orally.

Primary efficacy will be assessed by the proportion of participants who maintain TSH within the predefined target range (0.1–0.5 mIU/L) for the entire study period without any dose adjustments of levothyroxine or liothyronine.

Secondary efficacy parameters include the absolute change from baseline in serum FT3 and FT4 concentrations, measured at weeks 4, 12, and 24 after initiation of tyrosine kinase inhibitor therapy. Health‑related quality of life will be evaluated using the EORTC QLQ‑C30 v3.0 questionnaire at the same time points. Serum LDL cholesterol will also be measured at weeks 4, 12, and 24. Genotypic analysis for the Thr92Ala polymorphism of the DIO2 gene will be performed to explore associations with hormone level changes.

Safety‑related efficacy assessments comprise the duration of excessive TSH suppression (TSH < 0.1 mIU/L), the cumulative time spent outside the target range (TSH > 0.5 mIU/L), time to first TSH deviation above 0.5 mIU/L, and the overall percentage of study time during which TSH values remain within the target interval.

Laboratory analyses will be conducted using validated immunoassays for thyroid hormones and lipid profiles. The EORTC QLQ‑C30 will be administered as a patient‑reported outcome instrument. Genetic testing will employ standard PCR‑based methods. Data will be analyzed using descriptive statistics for proportions, paired t‑tests or non‑parametric equivalents for hormone and lipid changes, and Kaplan‑Meier methods for time‑to‑event outcomes. All assessments will be performed at baseline and at the specified follow‑up weeks.