Niklson I A, Reimitz P E, Sennef C
Medical Research and Development Unit, N.V. Organon, Oss, The Netherlands.
Psychopharmacol Bull. 1997;33(1):41-51.
An important issue in judging the therapeutic potential of a new antidepressant drug is the effect size it generates in placebo-controlled trials which has to be compared with the effect of an active control. As this effect size tends to vary substantially it is not easy to predict the sample size in a clinical trial. We carried out two dose finding placebo- and imipramine-controlled, double-blind, multicenter and multinational trials (northern part of Europe) with a new psychotropic compound (NPC) currently being investigated in Phase II/III as a potential antidepressant in the indication major depressive disorder (MDD). Statistical analysis showed that the effect size of 150 mg per day imipramine was meager (1.04 points difference from placebo after 6 weeks according to total scores on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] based on the Intent-to-Treat group using last observation carried forward [LOCF] approach). To increase the discriminative power of the analysis we selected centers that were able to detect a difference of at least two points between imipramine and placebo on the HAM-D-17 total score at 6 weeks in the LOCF analysis (discriminative centers, DC). The other group of centers will be called non-discriminative centers (NDC). We found that 36 percent of centers were DC and recruited about 45 percent of patients. Further analysis revealed no statistically significant differences between the groups of centers concerning the important baseline characteristics of the patients. Also the pattern of reported adverse events did not differ between DC and NDC. We found a tendency for the DC to select more patients with recurrent illness, in particular with a previous good response to antidepressant therapy. The groups of centers differed in dropout rates for both active treatments (DC 19.3-20.4% vs. NDC 35.1-37.7%) but not for the placebo (DC 38.2% vs. NDC 30.5%) that could suggest that different treatment strategies were employed by different centers regarding the occurrence of adverse events with and without therapeutic effects.
判断一种新型抗抑郁药物治疗潜力的一个重要问题是其在安慰剂对照试验中产生的效应量，该效应量必须与活性对照的效应进行比较。由于这种效应量往往差异很大，因此在临床试验中预测样本量并不容易。我们开展了两项剂量探索性试验，以安慰剂和丙咪嗪为对照，双盲、多中心且跨国（欧洲北部）进行，研究一种新型精神药物化合物（NPC），该药物目前正处于II/III期研究阶段，作为重度抑郁症（MDD）适应症的潜在抗抑郁药。统计分析表明，每天150毫克丙咪嗪的效应量很小（根据使用末次观察向前结转[LOCF]方法的意向性治疗组在17项汉密尔顿抑郁评定量表[HAM-D-17]上的总分，6周后与安慰剂的差异为1.04分）。为了提高分析的辨别力，我们选择了在LOCF分析中能够在6周时检测到丙咪嗪和安慰剂在HAM-D-17总分上至少有2分差异的中心（辨别性中心，DC）。另一组中心将被称为非辨别性中心（NDC）。我们发现36%的中心是DC，招募了约45%的患者。进一步分析显示，在患者的重要基线特征方面，各中心组之间没有统计学上的显著差异。此外，DC和NDC报告的不良事件模式也没有差异。我们发现DC有选择更多复发性疾病患者的倾向，特别是之前对抗抑郁治疗有良好反应的患者。活性治疗的两组中心在脱落率方面存在差异（DC为19.3 - 20.4%，而NDC为35.1 - 37.7%），但安慰剂组没有差异（DC为38.2%，NDC为30.5%），这可能表明不同中心在处理有治疗效果和无治疗效果的不良事件发生情况时采用了不同的治疗策略。
