Multi-site Trial of Azathioprine Dosing in Crohn Disease
克罗恩病硫唑嘌呤给药的多中心试验
基本信息
- 批准号:6686485
- 负责人:
- 金额:$ 76.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-07-01 至 2007-04-30
- 项目状态:已结题
- 来源:
- 关键词:Crohn's disease adult human (21+) azathioprine children clinical research clinical trials corticosteroids dosage drug adverse effect drug metabolism enzyme activity gastrointestinal disorder chemotherapy gastrointestinal pharmacology guanine nucleotides human subject human therapy evaluation methyltransferase patient oriented research quality of life remission /regression thiopurine
项目摘要
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.
描述(由申请人提供):
硫唑嘌呤 (AZA) 是一种有效的类固醇节约疗法,用于治疗慢性活动性克罗恩病 (CD),并可防止类固醇诱导的缓解复发。然而,尽管对照试验有效,但没有关于如何优化治疗的剂量范围数据或前瞻性证据。现在人们认识到,AZA(一种无活性的前药)经历一系列酶促反应,产生 6-硫鸟嘌呤核苷酸 (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,这种代谢物无治疗活性且具有潜在的肝毒性。共显性遗传的多态性等位基因赋予高 (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)与治疗反应不佳相关。研究假设是,AZA 代谢的药物遗传学变异会影响 CD 治疗的短期和长期疗效和耐受性,并且可以根据基线 TPMT 活性和初始剂量递增后的早期代谢水平来预测最佳剂量和治疗反应。我们的目标是通过前瞻性评估 TPMT 酶活性水平和系列 6-TGN 测量来确定最佳剂量和反应预测,以管理成人和儿童类固醇难治性和类固醇依赖性 CD。为了检验这一假设,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到当前标准 AZA 治疗剂量为 2.5 mg/kg 或 AZA,剂量由其 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。我们的主要终点是确定固定和个体化 AZA 治疗在 16 周时无类固醇疾病缓解的频率上是否存在差异。次要终点将是评估 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的生活质量终点。将进行预测模型,以评估基于初始和诱导 TPMT 活性的反应性以及基于增量 AZA 剂量可实现的 6-TGN 和 6-MMPR 代谢物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
STEPHEN BRETT HANAUER其他文献
STEPHEN BRETT HANAUER的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('STEPHEN BRETT HANAUER', 18)}}的其他基金
Multi-site Trial of Azathioprine Dosing in Crohn Disease
克罗恩病硫唑嘌呤给药的多中心试验
- 批准号:
6760183 - 财政年份:2003
- 资助金额:
$ 76.23万 - 项目类别:
CDP571 IN MODERATE TO SEVERE CROHNS DISEASE
CDP571 患有中度至重度克罗恩病
- 批准号:
6304558 - 财政年份:1999
- 资助金额:
$ 76.23万 - 项目类别:
PHASE II STUDY OF BXT 51072 IN PATIENTS W/ ULCERATIVE COLITIS
BXT 51072 在溃疡性结肠炎患者中的 II 期研究
- 批准号:
6304548 - 财政年份:1999
- 资助金额:
$ 76.23万 - 项目类别:
CDP571 IN STEROID DEPENDENT PATIENTS W/ CROHNS DISEASE
CDP571 在类固醇依赖性克罗恩病患者中的应用
- 批准号:
6304557 - 财政年份:1999
- 资助金额:
$ 76.23万 - 项目类别:
PHASE II STUDY OF BXT 51072 IN PATIENTS W/ ULCERATIVE COLITIS
BXT 51072 在溃疡性结肠炎患者中的 II 期研究
- 批准号:
6264118 - 财政年份:1998
- 资助金额:
$ 76.23万 - 项目类别:
CDP571 IN MODERATE TO SEVERE CROHNS DISEASE
CDP571 患有中度至重度克罗恩病
- 批准号:
6264130 - 财政年份:1998
- 资助金额:
$ 76.23万 - 项目类别:
ISIS 2302 IN STEROID-DEPENDENT CROHN'S DISEASE
ISIS 2302 在类固醇依赖性克罗恩病中的应用
- 批准号:
6114531 - 财政年份:1998
- 资助金额:
$ 76.23万 - 项目类别:
CDP571 IN STEROID DEPENDENT PATIENTS W/ CROHNS DISEASE
CDP571 在类固醇依赖性克罗恩病患者中的应用
- 批准号:
6264129 - 财政年份:1998
- 资助金额:
$ 76.23万 - 项目类别:
ISIS 2302 IN STEROID-DEPENDENT CROHN'S DISEASE
ISIS 2302 在类固醇依赖性克罗恩病中的应用
- 批准号:
6275766 - 财政年份:1997
- 资助金额:
$ 76.23万 - 项目类别:
IV PHO IL10 IN PATIENTS WITH STEROID REFRACTORY CROHNS
IV PHO IL10 用于类固醇难治性克罗恩病患者
- 批准号:
5218344 - 财政年份:
- 资助金额:
$ 76.23万 - 项目类别: