Head-to-Head Comparison of an IGF-1R Inhibitor Versus Intravenous Glucocorticoid for Active Thyroid Eye Disease: Design of a Randomized Clinical Trial.

introductionThyroid eye disease (TED) is a disfiguring and potentially sight-threatening autoimmune orbital disorder. Intravenous glucocorticoid (IVGC) is the current first-line treatment for active, moderate-to-severe TED but its efficacy in reducing proptosis and diplopia is limited and inconsistent, with high relapse rates. In recent years, inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) have emerged as a novel therapeutic class for TED. Clinical studies have demonstrated that IGF-1R inhibitors can significantly reduce proptosis and improve overall disease activity in patients with active, moderate-to-severe TED. Although both therapies are available, no head-to-head clinical trial has directly compared IGF-1R inhibitors with IVGC. Therefore, this study aims to evaluate the efficacy and safety of an IGF-1R inhibitor compared with IVGC pulse therapy on proptosis in patients with active TED.

methodsThis is a multicenter, randomized, open-label, active-controlled phase 4 trial. Adults with active moderate-to-severe TED and baseline proptosis ≥ 16 mm in the study eye will be enrolled. Participants will be randomized 1:1 to receive either intravenous teprotumumab N01 (10 mg/kg initial dose on day 1, followed by 20 mg/kg at weeks 3, 6, 9, and 12) or IVGC pulse therapy (methylprednisolone 500 mg on day 1 and from week 1 to week 5, followed by 250 mg from week 6 to week 11). After completing the 12-week treatment period, participants will enter an extended treatment and observation phase. The primary outcome measure is the proportion of participants who achieve a ≥ 2-mm reduction in proptosis in the study eye at week 15. Key secondary outcome measures include the change from baseline in proptosis and the overall responder rate in the study eye at week 15. PLANNED OUTCOMES: This study plans to enroll approximately 92 participants with active TED. This trial is the first head-to-head clinical study comparing an IGF-1R (Insulin-like growth factor-1 receptor) inhibitor with IVGC. It aims to address the limitations of IVGC, including its uncertain efficacy on proptosis and diplopia, by utilizing a targeted approach to provide more comprehensive clinical evidence for TED treatment.

trial registrationClinicalTrials.gov identifier, NCT07265258 (RESTORE-4).