Multi-site Trial of Azathioprine Dosing in Crohn Disease

描述（由申请人提供）： 硫唑嘌呤（AZA）是治疗慢性活动性克罗恩病（CD）的一种有效的类固醇保留疗法，可预防类固醇诱导缓解的复发。然而，尽管在对照试验中有效，但没有剂量范围数据或关于如何优化治疗的前瞻性证据。现在认识到，AZA是一种无活性的前药，经过一系列酶促反应产生6-硫代鸟嘌呤核苷酸（6- TGN），被认为是活性但具有骨髓毒性的代谢物。在竞争性酶促途径中，硫嘌呤甲基转移酶（TPMT）催化6-甲基巯基嘌呤核糖核苷酸（6-MMPR）的形成，6-MMPR是治疗上无活性且具有潜在肝毒性的代谢物。共显性遗传的多态性等位基因赋予影响AZA的治疗反应和毒性的高（TPMTH）和低（TPMTL）功能性TPMT活性。回顾性观察表明，低水平的6-TGN代谢物（由于剂量不足或TPMT活性高）与治疗反应不良相关。研究假设是AZA代谢的药物遗传学变异性影响CD治疗的短期和长期疗效和耐受性，并且可以基于基线TPMT活性和初始剂量递增后的早期代谢物水平预测最佳剂量和治疗反应。我们的目的是通过前瞻性评估TPMT酶活性水平和系列6-TGN测量来确定最佳剂量和预测反应，以管理成人和儿童中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性CD的成人和儿童患者随机分配至当前标准AZA治疗（剂量为2.5mg/kg）或AZA（剂量由TPMT活性决定），随后进行调整以将6-TGN水平维持在拟定的治疗范围内。我们的主要终点将是确定在16周时，固定和个体化AZA治疗在无类固醇疾病缓解的频率上是否存在差异。次要终点是评估28周和52周时的缓解频率，并评估不良事件、皮质类固醇需求和健康相关生活质量终点。将进行预测模型，以评估基于初始和诱导型TPMT活性以及基于增量AZA给药可实现的6-TGN和6-MMPR代谢物的反应性。

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.