Background

A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia.

Methods

We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and ClinicalTrials.gov, NCT03110848.

Findings

Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02–0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups.

Interpretation

Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association.

Funding

Associazione Allievi Endocrinologia Pisana.

中文翻译：

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Graves 眼眶病他汀类药物 (STAGO)：一项 2 期、开放标签、适应性、单中心、随机临床试验

背景

他汀类药物对 Graves 眼眶病发展的保护作用表明他汀类药物可用于治疗该疾病。我们旨在评估在静脉糖皮质激素 (ivGC) 中添加他汀类药物阿托伐他汀对高胆固醇血症患者 Graves 眼眶病变结果的疗效。

方法

我们在意大利比萨的一家三级转诊医院进行了一项随机、开放标签、2 期、适应性、临床试验。低密度脂蛋白胆固醇浓度在 2·97 至 4·88 mmol/L 之间的中度至重度活动性 Graves 眼眶病患者符合纳入标准。使用基于计算机的系统，患者被随机分配 (1:1) 分为 11 个区组，每组 8 个组，分别为 ST 组或 NST 组。ST 组接受 ivGCs（甲基强的松龙 500 mg 每周一次，持续 6 周，然后每周一次 250 mg，持续 6 周）持续 12 周和口服阿托伐他汀（每天一次 20 mg）持续 24 周。NST组只接受ivGC方案。患者被告知分组分配；然而，眼科调查员对随机化不知情。主要终点是 Graves 的 改良意向治疗 (ITT) 人群（参加第 12 周访视的患者）在 24 周时眼眶病变结果（眼球突出、临床活动评分、眼睑孔径和复视的综合评估）。当受影响最严重的眼睛至少满足以下两个标准时，患者被认为是有反应的，并且两只眼睛的任何相同措施都没有恶化：(1) 眼球突出减少 2 毫米或更多，没有增加 2 毫米或更多在另一只眼睛；(2)临床活动评分降低2分以上；(3) 眼睑孔径减少2mm以上，另一只眼不增加2mm以上；(4) 复视消失或改善（由常转为无常、间断或无，或由无常转为间断或无）复视，(5)视力提高0·2位小数以上。该试验已在 EUDRACT，2018-001317-33 和 ClinicalTrials.gov，NCT03110848 注册。

发现

2020 年 6 月 1 日至 2020 年 11 月 30 日期间，对 119 名患者进行了纳入筛选，其中 88 名 (74%) 患者被纳入并随机分配到两个治疗组之一（44 [50%] 名到 ST 组和44 [50%] 到 NST 组）。8 名 (9%) 患者未参加为期 12 周的访问；80 (91%) 名患者（18 [23%] 名男性和 62 [78%] 名女性）被纳入改良 ITT 人群（ST 组 41 [51%] 名，NST 组 39 [49%] 名]。 ST 组（41 名患者中的 21 [51%]）在 24 周时 Graves 眼眶病综合评估应答者的比例高于 NST 组（39 名患者中的 11 [28%]；归因风险 0·23 [95%] CI 0·02–0·44]；p=0·042。安全性人群中 88 名患者中有 21 名 (24%) 发生了 26 次不良事件。每组 44 名患者中有 1 名 (2%) 需要停止治疗，

解释

在 ivGC 方案中添加口服阿托伐他汀可改善高胆固醇血症的中至重度活动性眼病患者的 Graves 眼眶病结果。未来的 3 期研究可能会招募患者，而不管低密度脂蛋白胆固醇浓度如何，都需要证实这种关联。

资金

Associazione Allievi Endocrinologia Pisana。