Comparative Study of Ultrasound-Guided Radiofrequency Ablation and Sodium Iodide (131I) in Treating Hyperthyroidism from Solitary Autonomous Thyroid Nodules

The primary objective of this study is to compare the one-year incidence of irreversible **hypothyroidism** following treatment with either radioactive iodine (RAI) or radiofrequency ablation (RFA) in patients with hyperactive thyroid nodules. This comparison is clinically relevant as it aims to determine the long-term thyroid function outcomes of these two treatment modalities, which are commonly used for managing hyperthyroidism caused by solitary autonomous thyroid nodules.

Secondary objectives include:

• Comparing the one-year outcomes of RFA and RAI treatments in terms of cure rate, nodal volume reduction, fractional nodal uptake, adverse effects, thyroid function-related quality of life, and costs.
• Assessing the cost-effectiveness of RFA compared to RAI one year post-treatment and over a 10-year period using a health economic state transition model.
• Evaluating the course of thyroid function and comparing the results of RFA and RAI treatments during a five-year follow-up.
• Assessing patient experiences and preferences for both RFA and RAI treatments.
• Comparing outcomes on thyroid function between local standard practices of RAI treatment and nationally standardized RAI treatment.
• Identifying facilitators and barriers for the implementation of RFA or RAI treatments in daily clinical practice beyond the controlled trial setting.
• Evaluating treatment-related thyroiditis.

The clinical trial involves participants diagnosed with **hyperactive thyroid nodules**. The study population includes both male and female subjects, aged over 18 years, who are not part of a vulnerable population. Participants are required to have hyperthyroidism or subclinical hyperthyroidism caused by a solitary hyperactive thyroid nodule, either in an otherwise normal thyroid gland or within a multinodular goitre. The diagnosis is confirmed through specific blood tests and imaging techniques. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants must be eligible for treatment with radioactive iodine (RAI) and radiofrequency ablation (RFA), and they must have signed informed consent. The selection criteria ensure that participants have a solitary hyperactive thyroid nodule confirmed by diagnostic scintigraphy and ultrasound, with specific characteristics regarding blood TSH levels, antibody status, and nodule size. Lifestyle considerations such as diet and physical activity are not detailed in the available data.

The clinical trial is designed to evaluate the efficacy of **radioactive iodine** (RAI) treatment compared to ultrasound-guided radiofrequency ablation (RFA) for patients with hyperactive thyroid nodules. This is a phase III, randomized, double-blind, controlled trial with a primary objective to compare the one-year incidence of irreversible hypothyroidism following either RAI or RFA treatment. The trial is expected to commence recruitment on October 1, 2024, and conclude by August 1, 2026. Participants will be randomly assigned to receive either RAI or RFA, with the intervention administered orally in the form of **sodium iodide (131I)** capsules.

The study will involve several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, presence of hyperthyroidism or subclinical hyperthyroidism due to a solitary hyperactive thyroid nodule, and a signed informed consent. Follow-up visits are scheduled at 6 weeks, and 3, 6, and 12 months post-treatment to assess primary and secondary endpoints, including the cumulative incidence of irreversible hypothyroidism, cure rate, thyroid nodule volume, and treatment-related adverse events. The end-of-study visit will occur at 12 months, with an extension of follow-up up to 5 years for long-term assessment of thyroid function and quality of life.

Participant involvement is expected to last for a minimum of one year, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will utilize validated questionnaires such as the ThyPro and EQ-5D-5L to evaluate thyroid-related quality of life and health outcomes. The study aims to provide comprehensive data on the cost-effectiveness and health care resource utilization associated with each treatment modality over the course of one year.

The clinical trial involves the use of **Sodium Iodide (131I)** as the experimental medication. This compound is administered in the form of a hard capsule, with a dosage range of 0.329 to 3.7 MBq per capsule. The route of administration is oral, and the maximum daily dose is set at 740 MBq. The treatment period is limited to a maximum of one day. The active substance, **Sodium Iodide (131I)**, is of chemical origin and is utilized for its radioactive properties in the treatment of hyperthyroidism caused by solitary autonomous thyroid nodules. The product is manufactured by GE Healthcare Limited and is identified by the ATC code V09FX03.

In addition to the experimental treatment, the study includes a comparator treatment using **Sodium Iodide (131I)** in a different pharmaceutical form. This form is identified by the code PHF00231MIG and is also administered orally. The maximum daily and total dose for this form is 740 MBq, with a treatment period of one day. The comparator serves to evaluate the efficacy of the experimental treatment against a standard radioactive iodine therapy. Both treatments are monitored for participant compliance, ensuring adherence to the dosing schedule and administration route.

Efficacy in the clinical trial titled "Ultrasound-guided Radiofrequency Ablation versus radioactive Iodine as treatment for Hyperthyroidism caused by Solitary Autonomous Thyroid Nodules (RABITO study)" will be assessed using both primary and secondary endpoints. The primary endpoint is the cumulative incidence of irreversible **hypothyroidism** within the first year following intervention. Irreversible primary hypothyroidism is defined by specific criteria, including symptomatic or asymptomatic elevation of TSH levels within a specified range for a set duration, confirmed by repeated measurements.

Secondary endpoints include a variety of measures to evaluate treatment efficacy and patient outcomes. These include the cure rate at one year, defined by the normalization of TSH, FT4, and FT3/T3 levels, and the assessment of thyroid nodule volume via ultrasound at baseline, 6, and 12 months. Fractional nodal uptake will be assessed by I-123 or I-131 scintigraphy at baseline and 12 months. Additionally, thyroid antibodies will be monitored at 0 and 12 months to evaluate treatment-related autoimmunity.

Other secondary endpoints involve the evaluation of treatment-related adverse events at multiple time points, thyroid-related quality of life using the ThyPro questionnaire, and overall health outcomes and quality of life assessed by the European QoL-5 Dimensions (EQ-5D-5L) questionnaire. The use of healthcare resources and cumulative costs will be tracked over the first year, with cost-effectiveness determined by incremental costs per quality-adjusted life year (QALY). The course of thyroid function will be monitored through TSH, FT4, and FT3 levels at baseline and during a one-year follow-up, with an extension up to five years. Short-term patient satisfaction will be assessed through interviews, a satisfaction questionnaire, and pain scoring using a visual analog scale (VAS).