Myers Evan R, Silva Susan G, Hafley Gail, Kunselman Allen R, Nestler John E, Legro Richard S
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC 27710, United States.
Contemp Clin Trials. 2005 Jun;26(3):271-80. doi: 10.1016/j.cct.2005.01.006.
Polycystic ovary syndrome (PCOS) affects approximately 5% of the female population, and is a leading cause of infertility, primarily secondary to anovulation. Clomiphene citrate has been standard therapy for ovulation induction in patients seeking pregnancy, but recent evidence suggests that insulin sensitizing agents such as metformin may also be effective. The National Institute of Child Health and Human Development's Reproductive Medicine Network has begun a randomized, double-blind trial of clomiphene vs. metformin vs. clomiphene plus metformin for the induction of ovulation in patients with PCOS seeking pregnancy, with live birth rate as the primary outcome. Because the available literature was largely limited to surrogate outcomes such as ovulation and pregnancy rates, we created a Markov model to derive estimates of likely live birth rates in each arm. Using these estimates, we then constructed an algorithm that allowed only two formal comparisons between the three arms. First, we assumed that combination therapy would have to be superior to the next best single-agent therapy in order to be preferred, because of complexity, costs, increased side effects, etc. If combination therapy is not superior to the next best single agent, then the only other comparison of interest is between the two single agent therapies. Because the third possible comparison, between the best and worst of the three therapies, is not clinically relevant, it can be eliminated from formal statistical consideration, with subsequent reduction in sample size. Based on the opinion of the Network Steering Committee that a 15% absolute difference in live birth rates would be clinically relevant, our methodology resulted in a sample size of 226 per arm, or a total of 678 subjects. The PPCOS trial should definitively answer the question of the relative efficacy of metformin, clomiphene, and combination therapy in the treatment of infertile women with PCOS.
多囊卵巢综合征（PCOS）影响着约5%的女性人群，是导致不孕的主要原因，主要继发于无排卵。枸橼酸氯米芬一直是寻求怀孕患者诱导排卵的标准疗法，但最近有证据表明，二甲双胍等胰岛素增敏剂可能也有效。美国国立儿童健康与人类发展研究所生殖医学网络已开始一项随机、双盲试验，比较氯米芬、二甲双胍以及氯米芬加二甲双胍对寻求怀孕的PCOS患者诱导排卵的效果，将活产率作为主要结局指标。由于现有文献大多局限于排卵和妊娠率等替代结局指标，我们创建了一个马尔可夫模型来估算每组可能的活产率。利用这些估算值，我们构建了一种算法，该算法仅允许对三组进行两次正式比较。首先，我们假设联合治疗由于复杂性、成本、副作用增加等原因，必须优于次优的单一药物治疗才能被选用。如果联合治疗不优于次优的单一药物治疗，那么唯一有意义的比较就是两种单一药物治疗之间的比较。由于三种治疗方法中最佳和最差之间的第三种可能比较在临床上不相关，因此可以从正式的统计考虑中排除，从而减小样本量。根据网络指导委员会的意见，活产率15%的绝对差异在临床上具有相关性，我们的方法得出每组样本量为226例，总共678名受试者。PPCOS试验应能明确回答二甲双胍、氯米芬和联合治疗在治疗PCOS不孕女性方面的相对疗效问题。
