Multi-site Trial of Azathioprine Dosing in Crohn Disease

描述(由申请人提供)： 硫唑嘌呤(AZA)是治疗慢性活动期克罗恩病(CD)的一种有效的非激素疗法，可防止类固醇诱导的缓解复发。然而，尽管在对照试验中有效，但没有剂量范围的数据或关于如何优化治疗的预期证据。目前认为，AZA是一种非活性的前体药物，它经历了一系列的酶反应，产生了6-硫代鸟嘌呤核苷酸(6-TGN)，被认为是一种活性的但具有髓毒性的代谢物。在竞争性的酶途径中，硫代嘌呤甲基转移酶(TPMT)催化形成6-甲基-硫代嘌呤核糖核苷酸(6-MMPR)，这些代谢物在治疗上没有活性，并且具有潜在的肝脏毒性。共显性遗传的多态等位基因赋予高(TPMTH)和低(TPMTL)功能性TPMT活性，影响AZA的治疗反应和毒性。回顾观察表明，低水平的6-TGN代谢物(由于剂量不足或TPMT活性高)与治疗反应差有关。研究假设是AZA代谢的药物遗传变异影响CD治疗的短期和长期疗效和耐受性，并且可以根据初始剂量递增后的基线TPMT活性和早期代谢物水平预测最佳剂量和治疗反应。我们的目标是通过前瞻性地评估TPMT酶活性水平和系列6-TGN测量来确定最佳剂量和预测疗效，以管理成人和儿童的类固醇难治性和类固醇依赖性CD。为了验证这一假设，我们提出了一项双盲多中心试验，将患有类固醇难治性和类固醇依赖的CD的成人和儿童患者随机分为两组，一组接受当前标准的AZA治疗，剂量为2.5 mg/kg，另一组为AZA，剂量由他们的TPMT活性确定，随后进行调整，以将6-TGN水平维持在建议的治疗范围内。我们的主要终点将是确定在16周时，固定AZA治疗和个体化AZA治疗在非类固醇疾病缓解频率方面是否存在差异。次要终点将是评估28周和52周的缓解频率，并评估不良事件、皮质类固醇需求和与健康相关的生活质量终点。根据初始和可诱导的TPMT活性以及基于AZA递增剂量的可实现的6-TGN和6-MMPR代谢物，将执行预测模型来评估响应性。

DESCRIPTION (provided by applicant): Azathioprine (AZA) is an effective steroid-sparing therapy for chronically active Crohn's Disease (CD) and prevents relapse of steroid-induced remissions. However, despite efficacy in controlled trials, there is no dose-ranging data or prospective evidence on how to optimize therapy. It is now recognized that AZA, an inactive pro-drug, undergoes a series of enzymatic reactions leading to 6-thioguanine nucleotides (6- TGN), considered the active but, myelotoxic, metabolites. In a competing enzymatic pathway, thiopurine methyltransferase (TPMT) catalyzes formation of 6-methyl-mercaptopurine ribonucleotides (6-MMPR), metabolites that are therapeutically inactive and potentially hepatotoxic. Co-dominantly inherited polymorphic alleles confer high (TPMTH) and low (TPMTL) functional TPMT activity that impact AZA's therapeutic response and toxicity. Retrospective observations suggest that low levels of 6-TGN metabolites (due to under-dosing or high TPMT activity) are associated with poor therapeutic response. The study hypotheses are that pharmacogenetic variability in the metabolism of AZA impacts short and long-term therapeutic efficacy and tolerance in the treatment of CD, and that optimal dosing and response to treatment can be predicted based upon baseline TPMT activity and early metabolite levels after initial dose-escalation. Our objective is to determine optimal dosing and prediction of response by prospectively assessing TPMT enzyme activity levels and serial 6-TGN measurements for the management of steroid refractory and steroid-dependent CD in adults and children. To test the hypothesis, we propose a double blind, multi-center trial randomizing adult and pediatric patients with steroid-refractory and steroid dependent CD to either current standard AZA therapy dosed at 2.5mg/kg, or AZA, at a dose determined by their TPMT activity, and subsequently adjusted to maintain the 6-TGN levels within the proposed therapeutic range. Our primary endpoint will be to determine if there is a difference between fixed and individualized AZA therapy in the frequency of steroid-free disease remissions at 16 weeks. Secondary endpoints will be to assess the frequencies of remissions at 28 weeks and 52 weeks and to assess adverse events, corticosteroid requirements, and health related quality of life endpoints. Predictive models will be performed to assess responsiveness based upon initial and inducible TPMT activity and achievable 6-TGN and 6-MMPR metabolite based upon incremental AZA dosing.