The Lancet Diabetes & Endocrinology ( IF 44.5 ) Pub Date : 2021-04-15 , DOI: 10.1016/s2213-8587(21)00056-5 George J Kahaly 1 , Raymond S Douglas 2 , Robert J Holt 3 , Saba Sile 3 , Terry J Smith 4
Background
Thyroid eye disease manifests inflammation and treatment-resistant proptosis and diplopia. Teprotumumab, an insulin-like growth factor-1 receptor inhibiting monoclonal antibody, was approved in the USA on Jan 21, 2020, on the basis of two randomised trials. In this analysis we evaluated the short-term and long-term aggregate response to teprotumumab from the two trials, focusing on proptosis and diplopia.
Methods
We analysed integrated outcomes and follow-up data from two randomised, double-masked, placebo-controlled, multicentre, trials done at a total of 28 academic referral tertiary specialised centres offering joint thyroid eye clinics, or orbital clinics or practices, or both, in Europe and the USA. Participants were adult patients with a diagnosis of Graves' disease and active moderate-to-severe thyroid eye disease (clinical activity score [CAS] ≥4). Patients received eight intravenous infusions of either teprotumumab (10 mg/kg body weight for the first infusion, 20 mg/kg for subsequent infusions) or placebo every 3 weeks. The final study visit was at week 24, 3 weeks after the final infusion. In our analysis, the prespecified primary outcome was the between-group difference from baseline to week 24 in the proportion of patients with a proptosis response (≥2 mm reduction in the study eye without similar deterioration in the fellow eye at week 24) stratified by tobacco non-use and current use. Secondary endpoints at week 24 were the proportion of patients with improved diplopia (≥1 Bahn–Gorman grade), an overall response (reduction of ≥2 mm in proptosis and reduction of ≥2 points in CAS), mean change from baseline in proptosis measurement in the study eye, mean change from baseline in Graves' ophthalmopathy quality of life (GO-QOL) questionnaire scores (overall, visual functioning, and appearance), and the proportion of patients with disease inactivation (ie, a CAS score of 0 or 1). We also assessed data for the primary and secondary outcomes by patient subgroups (tobacco use; age <65 years or older; sex; time to diagnosis; CAS score 4 or 5, or 6 or 7; and thyrotropin binding inhibiting immunoglobulin [TBII] concentration <10 IU/L or ≥10 IU/L) versus placebo. Additional outcomes included short-term and long-term responses at 7 weeks and 51 weeks after the final dose, and post-hoc assessments of disease severity (more severe baseline disease defined as proptosis ≥3 mm or constant or inconstant diplopia, or both, as compared with all others), and an ophthalmic composite outcome (improvement in ≥1 eye from baseline without deterioration in either eye in ≥2 of the following: absence of eyelid swelling; CAS ≥2; proptosis ≥2 mm; lid aperture ≥2 mm; diplopia disappearance or grade change; or improvement of 8 degrees of globe motility). All outcome endpoint analyses were done by intention-to-treat (ITT) except where noted.
Findings
The pooled ITT population consisted of 84 patients assigned teprotumumab and 87 assigned placebo. More patients receiving teprotumumab achieved a reduction of at least 2 mm in proptosis at week 24 versus placebo (65 [77%] of 84 patients assigned teprotumumab vs 13 [15%] assigned placebo; stratified treatment difference 63%, 95% CI 51–75; p<0·0001). Numbers-needed-to-treat (NNT) were 1·6 for proptosis response, 2·5 for diplopia response (treatment difference 39%, 95% CI 23–55), 1·7 for overall response (treatment difference 60%, 48–72), and 2·5 for disease inactivation (treatment difference 40%, 27–53); all p <0·0001. The post-hoc assessment of the composite outcome showed that it was reached by 68 (81%) patients in the teprotumumab group and 38 (44%) in the placebo group (NNT 2·5, treatment difference 40%, 95% CI 26–53; p<0·0001). There were significantly more proptosis responders with teprotumumab in all subgroups at week 24; the number of diplopia responders was also significantly higher with teprotumumab for all subgroups except tobacco users and patients with TBII less than 10 IU/L at baseline. Integrated treatment differences for proptosis ranged from 47% in tobacco users (95% CI 21–73, p=0·0015; NNT=2·1) to 83% in patients aged 65 years and older (60–100, p<0·0001; NNT=1·2), and for diplopia ranged from 29% in tobacco users (95% CI −3 to 62, p=0·086; NNT=3·4) to 47% in those with baseline CAS of 6 or 7 (95% CI 23–71, p=0·0002; NNT=2·1). All other integrated subgroup results were p≤0·033. Integrated responses were observed at 7 weeks and 51 weeks after final dose for proptosis in 62 (87%) of 71 patients and 38 (67%) of 57 patients respectively; for diplopia in 38 (66%) of 58 and 33 (69%) of 48 respectively; and for the composite outcome in 66 (92%) of 72 and 48 (83%) of 58, respectively. During the 24-week study, compared with placebo, there were moderate-to-large improvements with teprotumumab for GO-QOL total scores (19 vs 6, p<0·0001), visual scores (20 vs 7, p=0·0003), and appearance scores (18 vs 6, p=0·0003), respectively, which were maintained during follow-up. Of all adverse events during the treatment period, 63 (94%) of 67 patients with teprotumumab and 59 (98%) of 60 patients with placebo were mild to moderate (grade 1 or 2), with three (4%) serious adverse events related or possibly related to teprotumumab of diarrhoea, infusion reaction, and Hashimoto's encephalopathy (co-incident with confusion) leading to study discontinuation. Of the most commonly reported adverse events with teprotumumab, muscle spasm (18%, 95% CI 7·3–28·7), hearing loss (10%), and hyperglycaemia (8%, 1·7–15·0) had the greatest risk difference from placebo.
Interpretation
Teprotumumab markedly improved the clinical course of thyroid eye disease in all patient subgroups examined from the two trials, with most patients maintaining responses in the long-term. Analyses of the effect of teprotumumab retreatment on non-responders and those who flare after response, as well as further studies in a broader population of thyroid eye disease are ongoing.
Funding
Horizon Therapeutics.
中文翻译:
Teprotumumab 治疗活动性甲状腺眼病患者:来自两项随机、双盲、安慰剂对照、多中心试验的汇总数据分析、亚组分析和治疗后随访结果
背景
甲状腺眼病表现为炎症和难治性眼球突出和复视。Teprotumumab 是一种胰岛素样生长因子-1 受体抑制单克隆抗体,基于两项随机试验于 2020 年 1 月 21 日在美国获得批准。在这项分析中,我们评估了两项试验对 teprotumumab 的短期和长期总体反应,重点是眼球突出和复视。
方法
我们分析了两项随机、双盲、安慰剂对照、多中心试验的综合结果和随访数据,这些试验在总共 28 个学术转诊三级专业中心进行,提供联合甲状腺眼科诊所、眼眶诊所或实践,或两者兼而有之,在欧洲和美国。参与者是诊断为格雷夫斯病和活动性中度至重度甲状腺眼病(临床活动评分 [CAS] ≥ 4)的成年患者。患者每 3 周接受 8 次静脉输注 teprotumumab(第一次输注 10 mg/kg 体重,随后输注 20 mg/kg)或安慰剂。最后一次研究访问是在最后一次输注后第 24 周,即 3 周。在我们的分析中,预先指定的主要结果是从基线到第 24 周的组间差异,即按不使用烟草分层的有眼球突出反应的患者比例(在第 24 周时研究眼减少 ≥ 2 毫米,而对侧眼没有类似恶化)和目前的使用。第 24 周的次要终点是复视改善(≥ 1 Bahn-Gorman 等级)的患者比例、总体反应(眼球突出减少 ≥ 2 mm 和 CAS 中减少 ≥ 2 分)、眼球突出测量从基线的平均变化在研究眼中,格雷夫斯眼病生活质量 (GO-QOL) 问卷评分(总体、视觉功能和外观)与基线相比的平均变化,以及疾病失活患者的比例(即 CAS 评分为 0 或1)。我们还评估了患者亚组的主要和次要结局数据(烟草使用;年龄 <65 岁或以上;性别;诊断时间;CAS 评分 4 或 5,或 6 或 7;以及促甲状腺素结合抑制免疫球蛋白 [TBII] 浓度<10 IU/L 或 ≥10 IU/L) 与安慰剂。其他结果包括最终给药后 7 周和 51 周的短期和长期反应,以及疾病严重程度的事后评估(更严重的基线疾病定义为眼球突出≥3 mm 或恒定或不恒定的复视,或两者兼而有之,与所有其他人相比),以及眼科综合结果(从基线起 ≥ 1 只眼的改善,且任一只眼在以下 ≥ 2 项中没有恶化:没有眼睑肿胀;CAS ≥2;眼球突出 ≥2 毫米;眼睑孔径 ≥2 mm;复视消失或等级改变;或改善 8 度的眼球运动)。除非另有说明,所有结局终点分析均通过意向治疗 (ITT) 进行。
发现
合并的 ITT 人群由 84 名分配给 teprotumumab 的患者和 87 名分配给安慰剂的患者组成。更多的患者接受teprotumumab在第24周达到减少至少2mm的突眼与安慰剂(65 [77%] 84名患者分配teprotumumab VS13 [15%] 分配安慰剂;分层治疗差异 63%,95% CI 51–75;p<0·0001)。需要治疗的人数 (NNT) 是眼球突出反应 1·6,复视反应 2·5(治疗差异 39%,95% CI 23-55),总体反应 1·7(治疗差异 60%, 48-72),疾病灭活为2·5(治疗差异40%,27-53);所有 p <0·0001。复合结局的事后评估表明,teprotumumab 组 68 名 (81%) 患者和安慰剂组 38 名 (44%) 患者达到了这一目标(NNT 2·5,治疗差异 40%,95% CI 26 –53;p<0·0001)。在第 24 周时,所有亚组中使用 teprotumumab 的眼球突出反应明显更多;除烟草使用者和基线时 TBII 低于 10 IU/L 的患者外,所有亚组使用 teprotumumab 的复视反应者数量也显着增加。眼球突出的综合治疗差异范围从烟草使用者的 47%(95% CI 21-73,p=0·0015;NNT=2·1)到 65 岁及以上患者的 83%(60-100,p<0 ·0001;NNT=1·2),复视的范围从烟草使用者的 29%(95% CI -3 到 62,p=0·086;NNT=3·4)到基线 CAS 为 47% 6 或 7(95% CI 23–71,p=0·0002;NNT=2·1)。所有其他综合亚组结果均为 p≤0·033。71 名患者中的 62 名 (87%) 和 57 名患者中的 38 名 (67%) 分别在眼球突出的最终剂量后 7 周和 51 周观察到综合反应;58 人中的 38 人 (66%) 和 48 人中的 33 人 (69%) 分别为复视;72 人中的 66 人 (92%) 和 58 人中的 48 人 (83%) 分别为复合结局。在为期 24 周的研究中,与安慰剂相比,teprotumumab 的 GO-QOL 总分有中到大的改善(19vs 6, p<0·0001), 视觉评分 (20 vs 7, p=0·0003) 和外观评分 (18 vs 6, p=0·0003), 在随访期间保持不变。在治疗期间的所有不良事件中,teprotumumab 组 67 名患者中有 63 名 (94%) 和安慰剂组 60 名患者中有 59 名 (98%) 为轻度至中度(1 级或 2 级),有 3 名 (4%) 严重不良事件与导致研究终止的腹泻、输液反应和桥本脑病(同时发生意识模糊)的 teprotumumab 相关或可能相关。在teprotumumab最常报告的不良事件中,肌肉痉挛(18%,95% CI 7·3-28·7)、听力损失(10%)和高血糖(8%,1·7-15·0)有与安慰剂的最大风险差异。
解释
在两项试验中检查的所有患者亚组中,Teprotumumab 显着改善了甲状腺眼病的临床病程,大多数患者长期保持反应。teprotumumab 再治疗对无反应者和反应后复发者的影响分析,以及在更广泛的甲状腺眼病人群中的进一步研究正在进行中。
资金
地平线疗法。