A randomised, double-masked, placebo-controlled trial evaluating the efficacy and safety of teprotumumab for active thyroid eye disease in Japanese patients

Abstract

Background: Teprotumumab significantly improved proptosis and diplopia in patients with active, moderate-to-severe thyroid eye disease (TED) in previous North American and European studies. This is the first evaluation of efficacy and safety of teprotumumab for active, moderate-to-severe TED in Japanese patients.

Methods: This randomised, double-masked, placebo-controlled trial was conducted in 16 centres in Japan. Main inclusion criteria were as follows: age 20-80 years; Graves' disease, in a euthyroid or mild hypo/hyperthyroid state; clinical activity score (CAS) ≥3; moderate-to-severe TED; ≥3-mm increase in proptosis before TED onset and/or proptosis ≥18 mm at baseline; and TED duration ≤9 months. Patients were randomised (1:1, stratified by smoking status) to either teprotumumab or placebo. Patients received eight intravenous infusions, one every three weeks for 24 weeks. Patients, investigators, site personnel (except formulating pharmacists) were masked. Primary endpoint was proptosis responder rate (percentage of patients with ≥2-mm proptosis reduction from baseline) at week 24 in the intent-to-treat population. Adverse events were assessed in all patients. This trial was registered at Japan Registry for Clinical Trials (jRCT2031210453).

Findings: Fifty-four patients were randomised (teprotumumab, 27; placebo, 27) between February and November 2022. All patients completed the randomised period, although one teprotumumab patient and two placebo patients missed ≥2 doses. At week 24, the proportion of patients with proptosis response was higher in the teprotumumab group (89%, 24/27) compared with the placebo group (11%, 3/27), 95% confidence interval, 61-95; P<0.0001. Study drug-related adverse events (AEs) occurred in 14 patients (52%) in the teprotumumab group and two patients (7%) in the placebo group; hyperglycaemia-related events were reported in six (22%) and one patient (4%), and hearing impairment in four (15%) and one (4%) patient, respectively. Study drug-related serious AEs and deaths were not reported.

Interpretation: Teprotumumab significantly improved proptosis compared with placebo in Japanese patients with active TED. No study drug-related serious AEs were observed.

Funding: Horizon Therapeutics plc (now Amgen).

Keywords: Clinical activity score; Double-masked; Japanese; Placebo-controlled trial; Proptosis; Randomised; Teprotumumab; Thyroid eye disease.

Fig. 1

Disposition of patients in the OPTIC-J trial. The most common reason for screen failure was not meeting the inclusion criteria for clinical diagnosis of Graves’ disease associated with active TED with a CAS ≥3. Abbreviation: ITT, intent-to-treat; TEAE, treatment-emergent adverse event; TED, thyroid eye disease. ^†Patient did not receive study drug (teprotumumab) at weeks 15 and 21 due to an AE of neurosensory hypoacusis. ^§Patient did not receive study drug (placebo) at weeks 18 and 21 due to an AE of neurosensory hypoacusis. ^#Patient did not receive study drug (placebo) at weeks 15, 18, and 21.

Fig. 2

(A) Proportion of patients with proptosis response; (B) proportion of patients with overall response; (C) proportion of patients with clinical activity score (CAS) categorical response; (D) least squares mean (LSM) change in proptosis from the baseline (BL); (E) proportion of patients with diplopia response among patients with diplopia at baseline (teprotumumab, n=22; placebo, n=20); and (F) proportion of patients with complete diplopia response among patients with diplopia at baseline (teprotumumab, n=22; placebo, n=20). Error bars represent 95% confidence intervals.

Fig. 3

Least squares mean (LSM) changes from the baseline to week 24 in (A) overall Graves’ ophthalmopathy quality of life (GO-QOL) scores, (B) GO-QOL-visual function (VF) scores, and (C) GO-QOL-appearance (AP) scores; for teprotumumab n=27 and placebo n=27 at each visit. (D) Coronal T2-weighted fat-suppressed magnetic resonance images taken at the baseline (left) and week 24 visits (right) in a patient treated with teprotumumab, showing reduction in the cross-sectional areas and inflammation of the orbital fat and extraocular muscles in the study (right eye) and fellow eyes (left eye). The blue arrows indicate the superior rectus/levator palpebrae superioris muscles, the yellow arrows indicate the inferior rectus muscle, and the red arrows indicate the lateral rectus muscle. (E) The volumes of the orbital fat (OF) and inferior rectus (IR), superior rectus (SR), medial rectus (MR), and lateral rectus (LR) muscles and signal intensity ratio (SIR) measured on magnetic resonance images taken at the baseline and week 24 visits in the patient shown in (D). Error bars in (A–C) represent 95% confidence intervals.