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和钙在大肠中具有抗肿瘤作用。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学预防作用。肠肿瘤息肉（腺瘤）是公认的恶性前病变，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使用这些终点进行了几项化学预防试验，在这次再提交中，我们提出了一项多中心随机、双盲、部分因子试验，研究碳酸钙和维生素D预防大肠肿瘤息肉复发的疗效。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。每位受试者在研究开始前4个月内至少切除了一个大肠腺瘤，结肠镜检查显示结直肠粘膜完整，肠道内无已知息肉残留。参与者将同意避免在试验之外服用研究药物，并将在为期3个月的安慰剂磨合期进行初步观察，在此期间将评估研究的适用性。合适的受试者将以2 × 2因子的方式随机分配到碳酸钙（1200mg钙/天）、维生素D （1000iu /天）、两种药物或安慰剂。由于许多妇女可能会拒绝放弃补钙，我们将为妇女提供随机选择单独补钙或补钙加维生素d的选择。结肠镜随访将在资格检查后3年或5年进行，根据每位受试者的医生的计划。作为安全措施，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。我们预计招募约2456名参与者，达到共1966名随机受试者。在关于事件发生率和研究行为的保守假设下，我们将有超过89%的能力检测到维生素D与安慰剂相比腺瘤复发率降低20%，85%的能力检测到钙加维生素D与单独钙相比腺瘤复发率降低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.