BACKGROUND Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).

中文翻译：

---

Teprotumumab用于治疗活动性甲状腺眼疾病。

背景技术甲状腺眼病是使眼周疾病变得虚弱，毁容和潜在致盲的疾病，目前尚无食品和药物管理局批准的医学治疗方法。有力的证据表明胰岛素样生长因子I受体（IGF-IR）参与了该病的发病过程。方法在一项随机，双掩蔽，安慰剂对照的3期多中心试验中，我们以1：1的比例分配患有活动性甲状腺眼疾病的患者接受IGF-IR抑制剂teprotumumab静脉输注（每公斤体重10毫克）第一次输注的重量，随后输注的重量为每公斤20 mg）或安慰剂，每3周一次，持续21周；该分析的最后一次试验访问是在第24周。主要结果是在第24周出现了眼球突出反应（眼球突出减少≥2 mm）。在第24周时预先确定的次要结局为总体反应（临床活动评分降低≥2分，而眼球突出减少2毫米以上），临床活动评分0或1（表明无炎症或轻度炎症），试验访问（从基线到第24周）的平均眼球变化，复视反应（≥1级复视减少）以及Graves眼病特定生活质量的总体评分平均变化（GO -QOL）调查问卷（从基线到第24周；平均变化≥6分被认为具有临床意义）。结果teprotumumab组共41例，安慰剂组42例。在第24周时，使用teprotumumab的眼球突出患者的百分比高于使用安慰剂的患者（83％[34例患者] vs. 10％[4例患者，P <0.001），需要治疗的数量为1.36。teprotumumab的所有次要结局均明显好于安慰剂，包括总体缓解率（78％的患者[32]比7％[3]），临床活动评分0或1（59％[24]相对21％[ 9]），平均眼球变化（-2.82毫米--0.54毫米），复视反应（68％[28的19] vs. 29％[28的8]）以及整体GO-QOL的平均变化得分（13.79分vs.4.43分）（全部P≤0.001）。teprotumumab组中有6例接受眼眶成像的患者眼外肌，眼眶脂肪量或两者均减少。大多数不良事件为轻度或中度；teprotumumab组发生了两次严重事件，其中之一（输注反应）导致治疗中断。结论在活动性甲状腺眼疾病患者中，与安慰剂相比，teprotumumab的眼球突出，临床活动评分，复视和生活质量方面的结果更好。严重的不良事件很少见。（由Horizo​​n Therapeutics资助; OPTIC ClinicalTrials.gov编号NCT03298867和EudraCT编号2017-002763-18。）