Long-term efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis: an interim analysis of the phase 3 U-ACTIVATE long-term extension study.

Here, we report interim results after 3 years of total treatment.

在这里，我们报告了总治疗3年后的中期结果。

Methods

U-ACTIVATE is an ongoing, 288-week, phase 3, long-term extension study done at 307 centres across 43 countries (active sites on Dec 31, 2021, are presented as part of this interim analysis) and began on Jan 31, 2017.

U-ACTIVATE 是一项正在进行中的、为期288周的、第3阶段、长期扩展研究，在43个国家的307个中心进行（2021年12月31日活跃的站点作为本次中期分析的一部分），并于2017年1月31日开始。

In brief, patients aged 16-75 years with a confirmed diagnosis of moderately to severely active ulcerative colitis for 90 days or more, an adapted Mayo score of 5-9, and an endoscopic subscore of 2 or 3 were eligible for the upadacitinib induction studies; patients who had a clinical response in the induction studies were eligible to enter the U-ACHIEVE maintenance study.

简而言之，年龄在16-75岁之间，确诊为中度至重度活动性溃疡性结肠炎90天或以上，适应性Mayo评分为5-9，内镜下评分为2或3的患者符合upadacitinib诱导研究的资格；在诱导研究中有临床反应的患者有资格进入U-ACHIEVE维持研究。

Individuals who completed the U-ACHIEVE maintenance study were subsequently eligible for inclusion in the efficacy population of this long-term extension study.

完成U-ACHIEVE维持研究的个体随后有资格被纳入本长期扩展研究的有效性人群。

Patients in clinical remission per adapted Mayo score at week 52 of the maintenance study could continue their double-masked treatment upon entering the long-term extension study.

在维持研究第52周时根据改良Mayo评分处于临床缓解状态的患者，在进入长期扩展研究时可以继续进行双盲治疗。

Patients not in clinical remission originally randomly assigned to upadacitinib 15 mg were eligible to escalate to upadacitinib 30 mg, those originally randomly assigned to upadacitinib 30 mg continued on upadacitinib 30 mg, and those originally assigned to placebo were eligible to escalate to upadacitinib 15 mg in a masked way.

最初未达到临床缓解的患者，随机分配到15 mg upadacitinib的，有资格增加剂量至30 mg upadacitinib；最初随机分配到30 mg upadacitinib的继续使用30 mg upadacitinib；最初分配到安慰剂的患者有资格以盲法方式增加剂量至15 mg upadacitinib。

We present data from weeks 48 and 96 of the long-term extension period.

我们展示了长期扩展期第48周和第96周的数据。

Key efficacy outcomes were clinical remission (per adapted Mayo score), endoscopic remission, maintenance of clinical remission, and maintenance of endoscopic remission, and are presented for those patients who had a clinical response after 8 weeks of upadacitinib 45 mg induction, completed 52 weeks of maintenance (U-ACHIEVE maintenance), and subsequently entered the long-term extension.

主要疗效结果包括临床缓解（根据改良的Mayo评分）、内镜缓解、维持临床缓解和维持内镜缓解，并为那些在使用45 mg upadacitinib诱导治疗8周后有临床反应、完成52周维持治疗（U-ACHIEVE维持）并随后进入长期扩展研究的患者呈现。

Safety outcomes were treatment-emergent adverse events and adverse events of special interest, which were prespecified and were recorded in two populations: one comprising patients who received at least one dose of study drug in the long-term extension study and the other comprising all patients in the maintenance or long-term extension studies.

安全性结果包括治疗后出现的不良事件和特别关注的不良事件，这些是预先设定的，并记录在两个群体中：一个包括至少接受一次研究药物长期扩展研究剂量的患者，另一个包括所有在维持或长期扩展研究中的患者。

Our primary approach for efficacy analysis was as-observed (ie, all observed data were used without imputation for missing data until patients switched to a different dose during the long-term extension study).

我们的主要疗效分析方法是按观察到的数据进行（即，在患者在长期扩展研究中转换到不同剂量之前，使用所有观察到的数据，不进行缺失数据的估算）。

This study is registered with ClinicalTrials.gov (NCT03006068).

该研究已在ClinicalTrials.gov上注册（NCT03006068）。

Results

414 patients from the phase 3 upadacitinib U-ACHIEVE maintenance study were eligible to enter this long-term extension study for assessment of efficacy endpoints following treatment with upadacitinib.

第三阶段upadacitinib U-ACHIEVE维持研究中的414名患者符合资格进入这项长期扩展研究，以评估接受upadacitinib治疗后的疗效终点。

Of these individuals, 369 patients (231 [63%] male individuals and 138 [37%] female individuals) were treated with upadacitinib in the long-term extension study: 142 patients with upadacitinib 15 mg and 227 with upadacitinib 30 mg.

在这些个体中，有369名患者（231名[63%]男性和138名[37%]女性）在长期扩展研究中接受了upadacitinib治疗：142名患者接受upadacitinib 15 mg治疗，227名接受upadacitinib 30 mg治疗。

In the as-observed population, 84 (71%) of 118 patients receiving upadacitinib 15 mg were in clinical remission at week 48, as were 130 (67%) of 193 receiving upadacitinib 30 mg; by week 96, 69 (76%) of 91 patients receiving upadacitinib 15 mg and 104 (74%) of 141 of those receiving upadacitinib 30 mg were in clinical remission.

在观察到的患者群体中，118名接受15毫克乌帕替尼治疗的患者中有84名（71%）在第48周时临床缓解，而接受30毫克乌帕替尼治疗的193名患者中有130名（67%）达到临床缓解；到第96周时，接受15毫克乌帕替尼治疗的91名患者中有69名（76%），接受30毫克乌帕替尼治疗的141名患者中有104名（74%）仍处于临床缓解状态。

Most patients who entered the long-term extension in clinical remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 62 [81%] of 77 and upadacitinib 30 mg 90 [81%] of 111; week 96 upadacitinib 15 mg 50 [78%] of 64 and upadacitinib 30 mg 69 [84%] of 82).

大多数进入长期扩展研究并处于临床缓解状态的患者在观察分析中保持了缓解状态（第48周时，15毫克乌帕替尼的77名患者中有62名[81%]，30毫克乌帕替尼的111名患者中有90名[81%]；第96周时，15毫克乌帕替尼的64名患者中有50名[78%]，30毫克乌帕替尼的82名患者中有69名[84%]）。

In the as-observed population, 60 (49%) of 123 patients receiving upadacitinib 15 mg and 93 (46%) of 202 receiving upadacitinib 30 mg were in endoscopic remission at week 48; by week 96, 45 (47%) of 95 patients receiving upadacitinib 15 mg and 69 (45%) of 153 receiving upadacitinib 30 mg were in endoscopic remission.

在按观察到的人群中，123名接受15毫克乌帕替尼治疗的患者中有60名（49%），以及202名接受30毫克乌帕替尼治疗的患者中有93名（46%）在第48周时内镜下缓解；到了第96周，95名接受15毫克乌帕替尼治疗的患者中有45名（47%），以及153名接受30毫克乌帕替尼治疗的患者中有69名（45%）处于内镜下缓解状态。

Most patients who entered the long-term extension in endoscopic remission maintained it in the as-observed analysis (week 48 upadacitinib 15 mg 28 [70%] of 40 and upadacitinib 30 mg 51 [76%] of 67; week 96 upadacitinib 15 mg 20 [65%] of 31 and upadacitinib 30 mg 37 [73%] of 51).

大多数进入长期扩展研究并处于内镜下缓解状态的患者在按观察到的分析中维持了缓解状态（第48周时，15毫克乌帕替尼的28名患者中有20名[70%]，30毫克乌帕替尼的67名患者中有51名[76%]；第96周时，15毫克乌帕替尼的31名患者中有20名[65%]，30毫克乌帕替尼的51名患者中有37名[73%]）。

In the long-term extension-only safety analysis, we assessed data from 467 patients, representing 1027·9 patient-years of continuous long-term extension exposure on a consistent upadacitinib dose.

在长期扩展的安全性分析中，我们评估了467名患者的资料，代表了在一致的upadacitinib剂量下连续长期扩展暴露的1027.9患者年。

Treatment-emergent adverse events were recorded at 238·5 events per 100 patient-years for upadacitinib 15 mg and 233·4 events per 100 patient-years for upadacitinib 30 mg.

治疗后出现的不良事件记录为每100患者年238.5事件对于upadacitinib 15 mg和每100患者年233.4事件对于upadacitinib 30 mg。

Event rates of serious treatment-emergent adverse events were 11·7 events per 100 patient-years for upadacitinib 15 mg and 12·4 events per 100 patient-years for upadacitinib 30 mg.

严重治疗相关不良事件的发生率为每100患者年11.7次对于upadacitinib 15 mg和每100患者年12.4次对于upadacitinib 30 mg。

The most common adverse events of special interest were hepatic disorder, lymphopenia, creatine phosphokinase elevation, serious infection, neutropenia, and herpes zoster.

特别关注的不良事件中，最常见的是肝功能障碍、淋巴细胞减少症、肌酸磷酸激酶升高、严重感染、中性粒细胞减少症和带状疱疹。

Three treatment-emergent adverse events leading to death were reported in the long-term extension-only safety population.

在长期扩展安全性人群中报告了三例导致死亡的治疗后不良事件。

interpretation

This interim analysis supports the positive long-term risk-benefit profile for upadacitinib 15 mg and 30 mg among patients with moderately to severely active ulcerative colitis.

这项中期分析支持了对于中度至重度活动性溃疡性结肠炎患者，15毫克和30毫克upadacitinib具有积极的长期风险-效益比。

funding

AbbVie.

艾伯维公司。