Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II).
Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II).
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DOI：
10.1136/gutjnl-2017-314562
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发表时间：
2019-01
期刊：
影响因子：
24.5
通讯作者：
Schreiber S
中科院分区：
文献类型：
--
作者：
Danese S;Vermeire S;Hellstern P;Panaccione R;Rogler G;Fraser G;Kohn A;Desreumaux P;Leong RW;Comer GM;Cataldi F;Banerjee A;Maguire MK;Li C;Rath N;Beebe J;Schreiber S
中和促炎性白细胞介素-6（IL-6）可有效治疗克罗恩病（CD）。报告了PF-04236921（一种抗IL-6抗体）在成人CD患者中的作用。筛选期为4周，治疗期为12周的双盲、剂量范围探索试验。诱导后，患者进入28周随访或48周开放标签扩展期（OLE）和28周随访。纳入了确诊CD和对抗肿瘤坏死因子（TNF）治疗反应不足的成人。诱导研究：249例患者以1：1：1：1的比例随机分配至安慰剂组，在第1天和第28天皮下注射PF-04236921 10、50或200 mg。OLE研究：PF-04236921 50 mg，每8周一次，最多6次给药，随后进行28周随访。247例患者在诱导研究中接受随机化和治疗。在另一项研究（NCT 01405196）中，由于安全性结果而停用200 mg剂量，未纳入主要疗效分析。第8周（49.3% vs 30.6%，P<0.05）和第12周（47.4% vs 28.6%，P<0.05）时，PF-04236921 50 mg组的克罗恩病活动指数（CDAI）-70缓解率显著高于安慰剂组，并符合主要终点。PF-04236921 50 mg组和安慰剂组第12周CDAI缓解率分别为27.4%和10.9%（差异16.5%; P<0.05）。191例受试者在OLE中接受治疗。两项研究中常见的治疗后出现的严重不良事件包括CD恶化、腹痛和鼻咽炎。PF-04236921 50 mg在抗TNF治疗失败后的难治性中重度CD患者中诱导临床应答和缓解。观察到GI脓肿和穿孔，这是未来临床开发中的一个特别关注点。NCT 01287897和NCT 01345318。
Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported. Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up. 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis. PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development. NCT01287897 and NCT01345318.
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