Aspirin/Folate Prevention of Large Bowel Polyps

描述(申请人提供)：本次重新提交的申请是对CA59005“阿司匹林/叶酸预防大肠息肉”的续展申请，这是一项随机、双盲、安慰剂对照试验，旨在评估阿司匹林和/或叶酸补充剂在有大肠肿瘤病史的受试者中预防大肠腺瘤的有效性。这项研究在析因设计中比较了两种剂量的阿司匹林(81毫克或325毫克)与安慰剂和叶酸(每天1毫克)和安慰剂。受试者在研究进入后36个月接受结肠镜检查随访，并被邀请在额外的结肠镜检查周期中继续随机叶酸治疗和/或随访。这项试验表明，服用小剂量阿司匹林有显著的好处。叶酸治疗的结果尚未报告；非盲法分析将在研究安全和数据监测委员会主席给研究部门执行秘书的保密信中发送。我们现在正在制定计划，停止延长叶酸治疗。利用这项申请所筹得的资金，我们建议在随机阿司匹林治疗结束后，完成对受试者一个监测周期的观察跟踪，并进行结直肠癌发生和阿司匹林化学预防的分子研究。这些研究将涉及在基线和阿司匹林治疗期间诊断的腺瘤的增殖、凋亡、分化、炎症和Wnt信号的测量。我们还建议结合哈佛大学公共卫生学院最近完成的临床试验进行叶酸分析，重点是对经常饮酒的个人补充叶酸的效果进行随机评估。我们的科学目标是：1)评估随机分配给阿司匹林或安慰剂与腺瘤风险的关系，同时考虑到在这一后期非甾体抗炎药的使用；2)评估随机阿司匹林治疗对治疗过程中发生的腺瘤分子标志物的影响；3)研究基线腺瘤分子标志物的分子流行病学；以及4)评估叶酸治疗对饮酒受试者腺瘤发生的影响。

DESCRIPTION (provided by applicant): This resubmitted application is for a renewal to CA59005, "Aspirin/Folate Prevention of Large Bowel Polyps," a randomized, double blind, placebo-controlled trial to evaluate the effectiveness of aspirin and/or folate supplementation in preventing adenomas of the large bowel among subjects with a history of these tumors. The study compared two aspirin doses (81 mg or 325 mg dally) versus placebo and folate (1 mg daily) versus placebo in a factorial design. Subjects underwent colonoscopic follow-up 36 months after study entry and were invited to continue randomized folate treatment and/or follow-up during an additional colonoscopic surveillance cycle. The trial showed a significant benefit with low dose aspirin. Results for folate treatment have not yet been reported; unblinded analyses will be sent in a confidential letter from the chair of the study's Safety and Data Monitoring Committee to the executive secretary of the study section. We are now making plans to discontinue the extended folate treatment. With the funds sought in this application, we propose to complete observational follow-up of subjects for one surveillance cycle after the end of randomized aspirin treatment and to conduct molecular studies of colorectal carcinogenesis and aspirin chemoprevention. These investigations will involve measurement of proliferation, apoptosis, differentiation, inflammation and Wnt signaling in adenomas that were diagnosed at baseline and during aspirin treatment. We also propose to conduct a combined folate analysis with the clinical trial recently completed by the Harvard School of Public Health, with a focus on the randomized assessment of the effect of folate supplementation among individuals who regularly consume alcohol. Our scientific aims are: 1) to assess the association between randomized assignment to aspirin or placebo and adenoma risk in the 3 to 5 year period after the end of randomized aspirin treatment, taking into account NSAID use during this later period, 2) to assess the effect of randomized aspirin treatment on the molecular markers in adenomas occurring while on treatment, 3) to study the molecular epidemiology of the molecular markers in baseline adenomas and 4) to assess the effect of folate treatment on adenoma occurrence among study subjects who drink alcohol.