延长阿达木单抗在静止期克罗恩病患者中的给药间隔：实用随机非劣效性LADI研究方案
Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.
作者信息
Smits L J T, Pauwels R W M, Kievit W, de Jong D J, de Vries A C, Hoentjen F, van der Woude C J
机构信息
Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands.
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
出版信息
BMJ Open. 2020 May 26;10(5):e035326. doi: 10.1136/bmjopen-2019-035326.
INTRODUCTION
Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).
METHODS AND ANALYSIS
The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.
ETHICS AND DISSEMINATION
The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences.
TRIAL REGISTRATION NUMBERS
EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).
引言
阿达木单抗对克罗恩病（CD）患者维持缓解有效，剂量为每2周皮下注射40mg。然而，阿达木单抗存在（长期）不良事件且成本高昂。本研究的目的是证明与标准的每两周一次（EOW）给药相比，疾病活动度引导下延长阿达木单抗给药间隔具有非劣效性和成本效益。
方法与分析
延长阿达木单抗给药间隔（LADI）研究是一项务实的、多中心的、开放标签的随机对照非劣效性试验。如果持续性（>8周）病情复发的累积发生率差异不超过15%的非劣效性界值，则达到非劣效性。将纳入174例接受阿达木单抗维持治疗且处于长期（>9个月）临床和生化缓解状态的CD患者（C反应蛋白（CRP）<10mg/L，粪便钙卫蛋白（FC）<150μg/g，哈维-布拉德肖指数（HBI）<5）。患者将按2:1随机分为干预组（延长阿达木单抗给药间隔）或对照组（阿达木单抗EOW）。干预组将把阿达木单抗给药间隔延长至每3周一次，24周后延长至每4周一次。医生将通过整体评估、HBI、CRP和FC每12周监测一次临床和生化疾病活动度。如出现病情复发，将增加给药剂量。病情复发定义为符合以下三项标准中的两项；FC>250μg/g，CRP≥10mg/l，HBI≥5。次要结局包括短暂性病情复发累积发生率、不良事件、成功降低剂量的预测因素以及成本效益。
伦理与传播
该研究已获得荷兰阿纳姆 - 奈梅亨医学伦理委员会批准（注册号NL58948.091.16）。研究结果将发表在同行评审期刊上，并在国际会议上展示。
试验注册号
欧洲临床试验数据库（EudraCT）注册号（2016 - 003321 - 42）；美国国立医学图书馆临床试验注册库（Clinicaltrials.gov）注册号（NCT03172377）；荷兰试验注册库（NTRID6417）。
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