Colorectal Chemoprevention with Calcium and Vitamin D

描述(申请人提供)：流行病学和实验数据表明，维生素D和钙在大肠中都有抗肿瘤作用。然而，需要来自临床试验的证据来澄清这两种药物的协同和独立的化学预防作用。肠道肿瘤性息肉(腺瘤)是公认的癌前病变，也是化学预防研究的有效终点。我们的研究联盟已经成功地利用这些终点进行了几项化学预防试验，在这次重新提交的报告中，我们提出了一项关于碳酸钙和维生素D预防大肠肿瘤性息肉复发的多中心随机、双盲、部分因素试验。这项研究将涉及北美的10个临床中心、一个病理中心和一个协调中心。每个受试者在进入研究前的4个月内将至少切除一个大肠腺瘤，并在结肠镜下对大肠粘膜进行完整的可视化，且肠道内没有已知的息肉。参与者将同意避免服用试验以外的研究试剂，并将首先在为期3个月的安慰剂磨合期内接受观察，在此期间将评估研究的适宜性。合适的受试者将被随机分为碳酸钙(1200毫克钙/天)、维生素D(1000IU/天)、这两种药物或安慰剂。由于许多女性可能会拒绝放弃补钙，我们将为女性提供选择，让她们随机接受单独补钙或补钙加维生素D。结肠镜检查将在合格考试后3年或5年进行，按照每个受试者的医生的计划。作为安全措施，血钙、肌酐和25-(OH)维生素D水平将在基线、1年和3年后随机获得。我们预计招募约2456名参与者，以达到总共1966名随机受试者。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%的力量检测到服用维生素D的腺瘤复发率比服用安慰剂的人减少了20%，有85%的力量检测到服用钙加维生素D的人比单独服用钙的人复发率减少了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.