Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial
Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial
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DOI：
10.1016/s0140-6736(17)32641-7
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发表时间：
2017-12-23
期刊：
影响因子：
168.9
通讯作者：
D'Haens, Geert
中科院分区：
文献类型：
--
作者：
Colombel, Jean-Frederic;Panaccione, Remo;D'Haens, Geert
背景肠道炎症的生物标志物，如粪便钙卫蛋白和C反应蛋白，已被推荐用于监测克罗恩病患者，但其在治疗决策中的使用是否改善了结果尚不清楚。我们的目的是比较内镜和临床结果的患者中重度克罗恩病谁是管理与严格控制的算法，使用临床症状和生物标志物，与患者管理与临床管理algorithm.Methods CALM是一个开放标签，随机，对照3期研究，在22个国家的74家医院和门诊中心，评估了成年患者（年龄18-75岁）患有活动性内镜克罗恩病（克罗恩病内镜严重指数[CDEIS] >6;在一个或多个具有溃疡的节段中CDEIS子评分之和>6），克罗恩病活动指数（CDAI）为150-450，取决于基线时泼尼松的剂量，并且之前没有使用免疫调节剂或生物制剂。患者以1：1的比例随机分配到严格控制组或临床管理组，< 70 kg or >在泼尼松诱导治疗8周后或更早（如果有活动性疾病），根据吸烟状态（是或否）、体重（≥ 70 kg）和疾病持续时间（2年）分层。在两组中，治疗以逐步方式递增，从无治疗至阿达木单抗诱导，随后每隔一周阿达木单抗，每周阿达木单抗，最后至每周阿达木单抗和每日硫唑嘌呤。这种递增是基于满足治疗失败标准，这在两组之间是不同的（随机分配之前和之后的严格对照组：粪便钙卫蛋白>= 250 μ g/g，C反应蛋白>= 5 mg/L，CDAI >= 150，或前一周使用泼尼松;随机分配之前的临床管理组：CDAI降低< 70 points compared with baseline or CDAI >200;随机分配之后的临床管理组：CDAI降低< 100 points compared with baseline or CDAI >= 200，或前一周使用泼尼松）。如果不符合失败标准，每周接受阿达木单抗和硫唑嘌呤或每周单独接受阿达木单抗的患者可能会降级。主要终点是随机分组后48周粘膜愈合（CDEIS < 4），无深部溃疡。在意向治疗人群中进行了主要和安全性分析。该试验已完成，并在ClinicalTrials注册。结果2011年2月11日至2016年11月3日，244例患者（平均病程：临床管理组，0.9年[SD 1.7];严格对照组，1.0年[2.3]）被随机分配至监测组（每组n=122）。临床管理组29例（24%）患者和严格对照组32例（26%）患者中止研究，主要是由于不良事件。严格控制组在第48周达到主要终点的患者比例（122例患者中的56例[46%]）显著高于临床管理组（122例患者中的37例[30%]），Cochran-Mantel-Haenszel检验校正的风险差异为16.1%（95%CI 3.9-28.3; p=0.010）。严格控制组122例患者中有105例（86%）和临床管理组122例患者中有100例（82%）报告了治疗后出现的不良事件;未发生治疗相关死亡。最常见的不良反应是恶心（122例患者中的21例[17%]），鼻咽炎（18%），头痛（18 [15%]）在严格控制组，克罗恩病恶化（122例患者中的35例[29%]），关节痛（19人[16%]），和鼻咽炎（18 [15%]）在临床管理组。解释CALM是第一个研究表明，及时升级与抗在早期克罗恩病患者中，基于临床症状结合生物标志物的肿瘤坏死因子治疗比单独的临床驱动决定产生更好的临床和内窥镜结果。未来的研究应该评估这种策略对长期结局的影响，如肠损伤，手术，住院和残疾。
Background Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm.Methods CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1: 1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (< 70 kg or >= 70 kg), and disease duration (2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin >= 250 mu g/g, C-reactive protein >= 5mg/L, CDAI >= 150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of < 70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of < 100 points compared with baseline or CDAI >= 200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS < 4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials. gov, number NCT01235689.Findings Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0.9 years [SD 1.7]; tight control group, 1.0 year [2.3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16.1% (95% CI 3.9-28.3; p=0.010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group.Interpretation CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability.