Colorectal Chemoprevention with Calcium and Vitamin D

描述（由申请人提供）：流行病学和实验数据表明，维生素D和钙在大肠中发挥抗肿瘤作用。 然而，需要临床试验的证据来阐明这两种药物的协同和独立的化疗预防作用。肠肿瘤性息肉（腺瘤）是公认的癌前病变和化学预防研究的有效终点。 我们的研究联盟已经成功地进行了几个化学预防试验，使用这些终点，在这个重新提交，我们提出了一个多中心的随机，双盲，部分析因试验的碳酸钙和维生素D在预防大肠肿瘤性息肉复发的疗效。 该研究将涉及北美的10个临床中心，一个病理中心和一个协调中心。 每例受试者将在进入研究前4个月内至少切除一个大肠腺瘤，结肠镜下完整显示结直肠粘膜，并且肠内无已知息肉残留。受试者将同意避免在试验外服用研究药物，并将在3个月的安慰剂导入期内进行初步观察，在此期间将评估研究的适用性。 合适的受试者将以2 × 2析因方式随机分配至碳酸钙（1200 mg钙/天）、维生素D（1000 IU/天）、两种药物或安慰剂组。由于许多女性可能拒绝放弃钙补充剂，我们将为女性提供随机选择，单独服用钙或钙加维生素D。 结肠镜随访将在资格检查后3年或5年进行，由每位受试者的医生计划。 作为安全性指标，将在基线、随机化后1年和3年获得血清钙、肌酐和25-（OH）维生素D水平。 我们预计入组约2456例受试者，达到总计1966例随机化受试者。 在关于事件发生率和研究进行的保守假设下，我们将有超过89%的把握检测到维生素D与安慰剂相比腺瘤复发减少20%，并且有85%的把握检测到钙+维生素D与单独钙相比复发减少25%。

DESCRIPTION (provided by applicant): Epidemiological and experimental data indicate that both vitamin D and calcium exert anti-neoplastic effects in the large bowel. However, evidence from clinical trials is required to clarify the synergistic and independent chemo preventive effects of these two agents. Neoplastic polyps (adenomas) of the bowel are recognized pre-malignant lesions and effective endpoints for chemoprevention studies. Our research consortium has successfully conducted several chemoprevention trials using these endpoints, and in this resubmission, we propose a multi-centered randomized, double blind, partial factorial trial of the efficacy of calcium carbonate and vitamin D in preventing the recurrence of neoplastic polyps of the large bowel. The study will involve 10 clinical centers in North America, a pathology center and a coordinating center. Each subject will have had at least one large bowel adenoma removed in the 4 months prior to study entry, with complete colonoscopic visualization of the colorectal mucosa and no known polyps remaining in the bowel. Participants will agree to avoid taking study agents outside the trial and will initially be observed in a 3- month placebo run-in period during which suitability for the study will be assessed. Suitable subjects will be randomized in a 2 x 2 factorial manner to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. Since many women may decline to forgo calcium supplementation, we will offer women the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up will occur at either 3 years or 5 years after the qualifying exam, as planned by each subject's physician. As safety measures, serum calcium, creatinine and 25-(OH) vitamin D levels will be obtained at baseline, and 1 year and 3 years after randomization. We anticipate enrolling about 2456 participants to reach a total of 1966 randomized subjects. Under conservative assumptions regarding event rates and study conduct, we will have greater than 89 percent power to detect a 20 percent reduction in adenoma recurrence with vitamin D versus placebo, and 85 percent power to detect a 25 percent reduction in recurrence with calcium plus vitamin D versus calcium alone.