Phase III Multicenter Trial Comparing Systematic Versus Serum Tg and RAI Scintigraphy-Guided Radioiodine Therapy in Intermediate-Risk Differentiated Thyroid Cancer

The primary objective of this multicentric phase III trial is to evaluate whether a strategy of **radioiodine (RAI)** treatment guided by a post-operative work-up is non-inferior to a systematic RAI treatment strategy in terms of achieving an excellent response rate at 3 years post-randomization in a "low-risk" subgroup of patients within the intermediate-risk differentiated thyroid cancer category. This is clinically relevant as it may allow for more personalized treatment approaches, potentially reducing unnecessary exposure to RAI and its associated risks.

Secondary objectives include:

• Comparing both strategies in terms of the rate of excellent response at 1 and 5 years, patient's quality of life, anxiety, impact of event scale, fear of cancer recurrence, salivary, nasal, and lachrymal toxicities, supplemental treatments performed within 5 years, and management cost over 5 years.
• Comparing diagnostic and post-therapeutic scintigraphy in the guided follow-up group.
• Assessing the added value of diagnostic RAI scintigraphy in decision-making for RAI treatment in the guided follow-up group.
• Evaluating the predictive value of post-operative serum thyroglobulin (Tg) level under Thyroxine and after recombinant human TSH on the presence of RAI-avid lesions on post-therapeutic scintigraphy and on the excellent response rate at 3 years in both groups.
• Assessing the excellent response rate at 3 and 5 years after randomization in cases of supplemental treatments.
• Collecting a tumor biobank for further translational research with somatic molecular markers such as BRAF and TERTp mutations.

The clinical trial involves **intermediate-risk differentiated thyroid cancer patients**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a **Performance Status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria include patients who have undergone total thyroidectomy with macroscopically complete tumor resection, with or without neck dissection, and have no known distant metastases. Post-operative LT4 treatment must have been initiated at least six weeks before randomization. Participants must have a normal post-operative neck ultrasound or, if doubtful, a negative cytology and normal Tg value in FNA washout fluid. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not disclosed additional information regarding the selection process or specific lifestyle factors.

The clinical trial is a multicentric phase III study designed to compare two strategies for the treatment of **intermediate-risk differentiated thyroid cancer**. The trial employs a randomized, controlled, and double-blind design to ensure the reliability and validity of the results. The primary objective is to evaluate whether a strategy of radioiodine (RAI) treatment guided by a post-operative work-up is non-inferior to a systematic RAI treatment strategy in terms of the excellent response rate at three years post-randomization in a low-risk subgroup of patients within the intermediate-risk category. The trial is expected to run from March 2020 to September 2027, with participant involvement lasting up to five years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as having undergone a total thyroidectomy with macroscopically complete tumor resection and being free of known distant metastases. Follow-up visits will occur annually for five years to monitor the response to treatment and assess secondary endpoints, including health-related quality of life (HRQoL), anxiety, and fear of cancer recurrence. The end-of-study visit will evaluate the primary endpoint, which is the rate of patients with an excellent response, defined by normal neck ultrasonography and specific thyroglobulin (Tg) levels, at three years post-randomization.

Participants are expected to remain in the study for the full duration unless conditions arise that necessitate early termination, such as the development of distant metastases or withdrawal of consent. The trial will also assess secondary endpoints, including the excellent response rate at one and five years, the impact of supplemental treatments, and the predictive value of somatic molecular markers. The study will utilize **sodium iodide (131I)** in capsule form, administered orally, with a maximum daily dose of 3.7 GBq. The trial's findings will contribute to optimizing treatment strategies for patients with intermediate-risk differentiated thyroid cancer.

The clinical trial involves the use of **Theracap 131**, a pharmaceutical product containing the active substance **sodium iodide (131I)**. This experimental medication is provided in the form of hard capsules, designed for **oral use**. The dosage of **Theracap 131** ranges from 37 to 5550 MBq per capsule, with a maximum daily and total dose of 3.7 GBq. The treatment period is limited to a maximum of one day. The product is manufactured by GE Healthcare B.V. and is authorized for use in the Netherlands. The administration of this medication is monitored to ensure compliance with the dosing schedule.

Another formulation of the same active substance, **THERACAP131, Iodure (131I) de sodium pour thérapie**, is also utilized in the trial. This product is similarly presented as hard capsules for **oral use**. The dosage and treatment parameters are consistent with the previously mentioned formulation, with a maximum daily and total dose of 3.7 GBq and a treatment period of one day. This formulation is produced by GE Healthcare SAS and is authorized for use in France. Both formulations are chemically identical and serve as either the test or comparator in the trial, depending on the specific study arm.

No non-experimental treatments, such as standard-of-care therapy or placebo, are specified in the trial data. Participant compliance with the dosing regimen is a critical component of the study, ensuring the integrity of the trial results. The trial aims to evaluate the efficacy of a systematic radioiodine administration strategy compared to a strategy guided by post-operative work-up in patients with intermediate-risk differentiated thyroid cancer.

Efficacy in this clinical trial will be assessed primarily through the rate of patients achieving an excellent response at 3 years post-randomization. The excellent response is defined by normal neck ultrasonography, **thyroglobulin** (Tg) levels on levothyroxine (LT4) being less than 0.2 ng/mL, absence of anti-thyroglobulin antibodies (TgAb), and no abnormalities on other imaging modalities if performed. Secondary endpoints include the excellent response rate at 1 and 5 years post-randomization, evaluated similarly for non-inferiority comparison. Additional secondary endpoints involve health-related quality of life (HRQoL), anxiety, and fear of cancer recurrence scores, which will be calculated using validated questionnaires at various timepoints, including inclusion, end of diagnostic assessment, end of treatment, 1 year, and 3 years. Toxicities affecting lachrymal, nasal, and salivary glands will also be assessed through specific questionnaires at these timepoints.

Supplemental treatments such as surgery or radioiodine (RAI) administration within 5 years post-randomization will be evaluated according to the 2015 American Thyroid Association (ATA) guidelines, categorizing responses as excellent, biochemical incomplete, structural incomplete, or indeterminate. The trial will also assess the costs from a French collective perspective, considering resources like consultations, hospitalizations, imaging exams, biological exams, transportation, study treatments, and sick leave related to thyroid cancer. The results of diagnostic and post-therapeutic scintigraphy will be analyzed in the guided follow-up group, along with the proportion of patients whose RAI treatment decisions were influenced by diagnostic RAI scintigraphy results. Post-operative serum Tg levels on LT4 and after recombinant human thyroid-stimulating hormone (rhTSH) will be measured to evaluate their predictive value for RAI-avid lesions and excellent response rates at 3 years. The predictive values of somatic molecular markers, particularly BRAF and TERT promoter mutations, on the risk of persistent disease will also be explored.