Background & Aims

New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy.

Methods

We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1.

Results

Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician’s global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea.

Conclusions

Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417

中文翻译：

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磷酸二酯酶 4 口服抑制剂阿普司特在活动性溃疡性结肠炎患者随机试验中的作用。

背景与目标

对常规治疗无反应或不耐受的溃疡性结肠炎 (UC) 患者需要新的口服治疗剂。

方法

我们对 3 个月或更长时间的活动性 UC 成人进行了一项双盲 2 期试验，这些患者对生物治疗没有反应，或因常规治疗失败、不能耐受或有常规治疗禁忌症。该研究在 14 个国家/地区的 61 个地点进行（筛选时间为 2015 年 1 月至 2017 年 5 月）。患者被随机分配到给予阿普司特 30 毫克（n = 57）、阿普司特 40 毫克（n = 55）或安慰剂（n = 58）的组中，每天两次，共 12 周；然后患者被随机分配到接受阿普司特的组，每天两次 30 或 40 毫克，再服用 40 周。在筛选阶段、第 12 周和第 52 周进行内窥镜检查并收集活组织检查。在整个研究过程中还收集并分析了血液和粪便样本。主要终点是第 12 周的临床缓解，

结果

在第 12 周，30 mg 阿普斯特组和安慰剂组分别有 31.6% 和 12.1% 的患者达到临床缓解（P = .01）。然而，40 mg 阿普斯特组中只有 21.8% 的患者在第 12 周达到临床缓解（P= .27 与安慰剂相比）。30 mg 和 40 mg 阿普斯特组之间临床缓解的差异与内窥镜改善的差异有关。两个 apremilast 组在 Mayo 评分组件（大便频率评分、直肠出血评分、医生的整体评估）方面比基线有相似的改善。与安慰剂组相比，30 毫克和 40 毫克阿普斯特组在第 12 周的 C 反应蛋白（通过高灵敏度血液测试测量）和粪便钙卫蛋白的中位数降低百分比更大。在第 52 周时，最初分配到 apremilast 30 mg 组的患者中有 40.4% 和最初分配到 apremilast 40 mg 组的患者中有 32.7% 实现了临床缓解。最常见的阿普斯特相关不良事件是头痛和恶心。

结论

尽管在该 2 期试验中未达到临床缓解的主要终点，但接受阿普斯特（30 毫克或 40 毫克）的活动性 UC 患者中有更大比例在 12 周时临床和内窥镜特征以及炎症标志物有所改善. 多达 40% 继续使用阿普司特直至该时间点的患者的临床缓解持续至第 52 周。ClinicalTrials.gov 编号：NCT02289417