Marder Stephen R, Eriksson Hans, Zhao Yudong, Hobart Mary
Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA, USA.
H. Lundbeck A/S, Valby, Denmark.
Acta Neuropsychiatr. 2020 Feb 14:1-6. doi: 10.1017/neu.2020.8.
We provide a closer look at the result of a randomised, placebo-controlled, active-reference (quetiapine XR), flexible-dose, 6-week study of brexpiprazole in schizophrenia, which did not meet its primary endpoint - change from baseline in Positive and Negative Syndrome Scale (PANSS) total score. We also investigate potential expectancy bias from the well-known side-effect profile of the active reference that could have affected the study outcome.
Pre-specified sensitivity analyses of the primary end point were performed using analysis of covariance (ANCOVA) last observation carried forward (LOCF) and observed cases (OC). Post hoc analyses of change from baseline in PANSS total score were performed using the mixed model for repeated measures approach with treatment groups split by having typical adverse events with potential for functional unblinding, for example, somnolence, increase in weight, dizziness, dry mouth and sedation.
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at week 6: LOCF, ANCOVA: -4.3 [95% CI (-8.0, -0.5), p = 0.0254]. OC, ANCOVA: -3.9 [95% CI (-7.3, -0.5), p = 0.0260]. Patients treated with brexpiprazole experiencing typical adverse events with potential for functional unblinding before or at Week 2 had a least square (LS) mean PANSS change of -29.5 (improvement), with a difference in change from baseline to Week 6 in PANSS total score between brexpiprazole and placebo of -13.5 [95% CI (-23.1, -4.0), p = 0.0057], and those who did not had an LS mean change of -18.9 and a difference between brexpiprazole and placebo of -2.9 [95% CI (-7.2, 1.4), p = 0.1809].
Pre-specified sensitivity analyses showed separation from placebo for brexpiprazole at Week 6. A post hoc analysis suggested a potential confounding of efficacy rating towards symptom improvement in patients who experience known side effects of quetiapine XR.
我们深入研究了一项关于布雷哌唑治疗精神分裂症的随机、安慰剂对照、活性对照（喹硫平缓释片）、灵活剂量、为期6周的研究结果，该研究未达到其主要终点——阳性和阴性症状量表（PANSS）总分相对于基线的变化。我们还调查了活性对照药物已知的副作用特征可能对研究结果产生影响的潜在期望偏差。
使用协方差分析（ANCOVA）的末次观察结转（LOCF）和观察病例（OC）对主要终点进行预先指定的敏感性分析。使用重复测量混合模型方法对PANSS总分相对于基线的变化进行事后分析，将治疗组按是否出现可能导致功能揭盲的典型不良事件（如嗜睡、体重增加、头晕、口干和镇静）进行划分。
预先指定的敏感性分析显示，在第6周时布雷哌唑与安慰剂分离：LOCF，ANCOVA：-4.3 [95%置信区间（-8.0，-0.5），p = 0.0254]。OC，ANCOVA：-3.9 [95%置信区间（-7.3，-0.5），p = 0.0260]。在第2周之前或第2周时出现可能导致功能揭盲的典型不良事件的布雷哌唑治疗患者，PANSS最小二乘（LS）平均变化为-29.5（改善），布雷哌唑与安慰剂在PANSS总分从基线到第6周的变化差异为-13.5 [95%置信区间（-23.1，-4.0），p = 0.0057]，而未出现此类事件的患者LS平均变化为-18.9，布雷哌唑与安慰剂的差异为-2.9 [95%置信区间（-7.2，1.4），p = 0.1809]。
预先指定的敏感性分析显示，在第6周时布雷哌唑与安慰剂分离。事后分析表明，对于经历喹硫平缓释片已知副作用的患者，疗效评定可能会受到症状改善方面的潜在混淆影响。
