We introduce the ReTRIACt Trial (NCT05579327) of tiratricol (Triac) for MCT8-deficiency, a rare X-linked disease resulting from disordered thyroid hormone transport and characterized by profound neurodevelopmental delay and features of chronic peripheral thyrotoxicosis. The ReTRIACt Trial aims to verify the effects of Triac observed in previous studies. It is a double-blind, randomized, multicenter, placebo-controlled study to evaluate the effects of Triac discontinuation in ≥16 evaluable male patients aged ≥4-years with confirmed MCT8-deficiency, maintained on a stable dose of Triac. Cohort A includes patients currently treated with Triac; Cohort B includes patients who are currently not receiving Triac. After demonstrating stable maintenance therapy with Triac within an open label Triac run in/titration phase, patients will be randomized to receive placebo (Triac withdrawal) or continue Triac. Patients remain on either placebo or Triac for 30 days or until they reach a biochemical threshold (serum total triiodothyronine [T3] >ULN) for rescue. Patients resume open label unblinded Triac treatment either at the end of the 30-day period or on reaching the biochemical rescue threshold. The primary efficacy endpoint is the proportion of patients who meet the biochemical rescue threshold during the 30-day treatment period. Secondary endpoints include effect of Triac on serum thyroid hormone, sex hormone binding globulin, Triac concentrations, time to meeting biochemical rescue threshold, and cardiovascular parameters. Exploratory endpoints include sleep measurements and pharmacokinetic analysis. The study requires only three visits to the hospital, with all remaining assessments being undertaken at home with the assistance of specialist domiciliary nurses and use of home-based clinical monitoring devices. The study is estimated to enroll patients in the second quarter of 2023. Given there is no registered therapy for MCT8-deficiency, the ReTRIACt Trial will aid in the regulatory process for approval of Triac for this disease.