Aspirin/Folate Prevention of Large Bowel Polyps

描述（由申请人提供）：此重新提交的申请是对CA 59005“阿司匹林/叶酸预防大肠息肉”的更新，这是一项随机、双盲、安慰剂对照试验，旨在评估阿司匹林和/或叶酸补充剂在预防有大肠腺瘤病史的受试者中大肠腺瘤的有效性。该研究在析因设计中比较了两种阿司匹林剂量（每天81 mg或325 mg）与安慰剂以及叶酸（每天1 mg）与安慰剂。受试者在研究入组后36个月接受结肠镜随访，并被邀请在额外的结肠镜监测周期内继续随机叶酸治疗和/或随访。该试验显示低剂量阿司匹林具有显著的益处。叶酸治疗的结果尚未报告;揭盲分析将通过研究安全性和数据监查委员会主席的机密信函发送给研究部门的执行秘书。我们现在正在计划停止延长叶酸治疗。利用本申请中寻求的资金，我们建议在随机阿司匹林治疗结束后完成一个监测周期的受试者观察性随访，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中的增殖、凋亡、分化、炎症和Wnt信号传导的测量。我们还建议结合哈佛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）评估随机分配至阿司匹林或安慰剂与随机化阿司匹林治疗结束后3至5年期间的腺瘤风险之间的关联，考虑到在该后期期间NSAID的使用，2）评估随机化阿司匹林治疗对治疗期间发生的腺瘤中的分子标志物的影响，3）研究基线腺瘤中分子标志物的分子流行病学和4）评估叶酸治疗对饮酒的研究受试者中腺瘤发生的影响。

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.