Background

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis.

Methods

The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4–17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)—using IVRS—to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557.

Findings

93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period.

Interpretation

Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis.

Funding

AbbVie.

中文翻译：

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阿达木单抗在中重度溃疡性结肠炎儿科患者中的疗效和安全性（ENVISION I）：一项随机、对照、3期研究

背景

溃疡性结肠炎儿童的生物治疗选择有限。本研究的目的是评估阿达木单抗治疗中重度溃疡性结肠炎儿童的安全性和有效性。

方法

双盲 ENVISION I 研究是在 10 个国家的 24 家医院进行的。尽管口服皮质类固醇或免疫抑制剂的同步治疗剂量稳定，但仍患有中度至重度溃疡性结肠炎的儿童（4-17 岁）被纳入研究。根据最初的研究设计，患者被随机分配到交互式语音应答系统 (IVRS) 接受高剂量诱导阿达木单抗（2·4 mg/kg [最大 160 mg] 在第 0 周和第 1 周）或标准剂量诱导阿达木单抗（第 0 周 2·4 mg/kg，第 1 周安慰剂）；两组在第 2 周接受 1·2 mg/kg（最大 80 mg）和在第 4 周和第 6 周接受 0·6 mg/kg（最大 40 mg）。在第 8 周出现部分梅奥评分 (PMS) 反应的患者（定义为两个或更多点的减少和 PMS 从基线减少≥30%）被随机分配（2:2：1)——使用 IVRS——接受高剂量维持阿达木单抗（每周 0·6 毫克/公斤）、标准剂量维持阿达木单抗（每隔一周 0·6 毫克/公斤）或安慰剂直至第 52 周（随机分配安慰剂组在试验中期停止，所有后续患者接受开放标签高剂量诱导阿达木单抗在诱导阶段随机化）。共同主要终点是第 8 周 PMS 缓解的患者比例（意向治疗 [ITT]-E 人群，不包括在诱导阶段未随机化的患者）和第 52 周完全梅奥评分 (FMS) 缓解的患者比例在第 8 周 PMS 应答者（维持 ITT-E [mITT-E] 人群）中，将合并阿达木单抗组（接受高剂量或标准剂量阿达木单抗的患者）和单独剂量组与外部成人安慰剂率进行比较。我们报告最终验证性分析的结果。该试验已在 ClinicalTrials.gov 注册，NCT02065557。

发现

2014 年 10 月 13 日至 2018 年 9 月 5 日期间，93 名儿童被招募到主要研究中（77 [83%] 被随机分配 [双盲] 接受高剂量或标准剂量诱导阿达木单抗；16 [17%] ] 在研究设计更改后接受开放标签高剂量诱导阿达木单抗）。在第 8 周，74 (80%) 名 PMS 反应儿童继续维持期。62 (84%) 名患者被随机分配接受高剂量或标准剂量的阿达木单抗维持治疗；12 (16%) 名患者接受安慰剂。在随机分配接受大剂量诱导阿达木单抗治疗的 ITT-E 人群中，与外用安慰剂相比，第 8 周 PMS 缓解的患者比例显着更高（47 人中的 28 人 [60%]） (19·8 %；p=0·0001)。标准剂量诱导阿达木单抗组的 30 名患者中有 13 名 (43%) 在第 8 周时 PMS 缓解，而外部安慰剂的缓解率为 19·8%，但这种差异不显着 (p=0·38)。同样，在 mITT-E 人群中，接受大剂量阿达木单抗维持治疗的患者（31 名患者中的 14 名 [45%]）与外用安慰剂相比，在第 8 周 PMS 应答者的第 52 周 FMS 缓解报告显着更高比例第 52 周（18·4%；p=0·0001）。标准剂量维持阿达木单抗组 31 名患者中有 9 名 (29%) 在第 52 周时 FMS 缓解，而外部安慰剂缓解率为 18·4%，但这种差异不显着 (p=0·38)。合并阿达木单抗组的缓解率明显优于外用安慰剂（第 8 周 PMS 缓解：77 名患者中的 41 [53%]；p<0·0001；第 52 周 FMS 缓解：62 名患者中的 23 名 [37%]；p=0·0001）。主要研究中的 93 名患者中有 21 名 (23%) 在任何阿达木单抗暴露期间发生了一个或多个治疗中出现的严重不良事件。最常见的不良事件是诱导期头痛、贫血和溃疡性结肠炎发作，维持期溃疡性结肠炎发作、头痛和鼻咽炎。

解释

在本研究中，接受阿达木单抗治疗的儿童报告了具有临床意义的缓解率和反应率。没有观察到新的安全性信号，表明阿达木单抗是中重度溃疡性结肠炎儿童的有效且安全的治疗选择。

资金

艾伯维。