Strawn Jeffrey R, Mills Jeffrey A, Cornwall Gary J, Mossman Sarah A, Varney Sara T, Keeshin Brooks R, Croarkin Paul E
1 Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati , College of Medicine, Cincinnati, Ohio.
2 Division of Child and Adolescent Psychiatry, Department of Pediatrics, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio.
J Child Adolesc Psychopharmacol. 2018 Feb;28(1):2-9. doi: 10.1089/cap.2017.0060. Epub 2017 Aug 28.
An increasing number of abandoned clinical trials have forestalled efforts to advance the evidence base for the treatment of mood and anxiety disorders in children and adolescents. With this in mind, we sought to present and validate a Bayesian approach for the reanalysis of summary data in abandoned clinical trials and to review and re-evaluate available pharmacokinetic, tolerability, and efficacy data from two large, randomized controlled trials of buspirone in pediatric patients with generalized anxiety disorder (GAD).
Prospective, randomized, parallel-group controlled trials of buspirone in pediatric patients with GAD as well as associated pharmacokinetic studies were identified and data were extracted. In addition to descriptive statistics, marginal posterior densities for each variable of interest were determined and a Monte Carlo pseudosample was generated with random draws obtained from the Student's t-distribution to assess, with inferential statistics, differences in variables of interest.
Buspirone was evaluated in one flexibly dosed (N = 227) and one fixed-dose (N = 341) trial in children and adolescents aged 6-17 years with a primary diagnosis of GAD. With regard to improvement in the sum of the Columbia Schedule for Affective Disorders and Schizophrenia GAD items, buspirone did not separate from placebo in the fixed-dose trial at low (95% CI: -0.78 to 2.39, p = 0.32) or high dose (95% CI: -0.87 to 1.87, p = 0.47) nor did it separate from placebo in the flexibly dosed study (95% CI: -0.3 to 1.9, p = 0.15). Drop out as a result of a treatment-emergent adverse event was significantly greater in buspirone-treated patients compared to placebo (p = 0.011). Side effects were consistent with the known profile of buspirone with lightheadedness occurring more frequently in buspirone-treated patients (p < 0.001).
Buspirone is well tolerated in pediatric patients with GAD, although two randomized controlled trials were underpowered to detect small effect sizes (Cohen's d < 0.15). Finally, Bayesian approaches may facilitate re-examination of data from abandoned clinical trials.
越来越多的临床试验被放弃，阻碍了为推进儿童和青少年情绪及焦虑障碍治疗的证据基础所做的努力。考虑到这一点，我们试图提出并验证一种贝叶斯方法，用于对已放弃临床试验中的汇总数据进行重新分析，并回顾和重新评估来自两项关于丁螺环酮治疗广泛性焦虑障碍（GAD）儿科患者的大型随机对照试验的现有药代动力学、耐受性和疗效数据。
确定了丁螺环酮治疗GAD儿科患者的前瞻性、随机、平行组对照试验以及相关的药代动力学研究，并提取了数据。除描述性统计外，确定了每个感兴趣变量的边际后验密度，并通过从学生t分布中随机抽取生成蒙特卡罗伪样本，以用推断统计评估感兴趣变量的差异。
在6至17岁初步诊断为GAD的儿童和青少年中，对丁螺环酮进行了一项灵活剂量（N = 227）试验和一项固定剂量（N = 341）试验。关于哥伦比亚情感障碍和精神分裂症GAD项目总和的改善情况，在固定剂量试验中，低剂量（95% CI：-0.78至2.39，p = 0.32）或高剂量（95% CI：-0.87至1.87，p = 0.47）时丁螺环酮与安慰剂无差异，在灵活剂量研究中也与安慰剂无差异（95% CI：-0.3至1.9，p = 0.15）。与安慰剂相比，丁螺环酮治疗的患者因治疗中出现的不良事件而退出的比例显著更高（p = 0.011）。副作用与丁螺环酮已知的情况一致，丁螺环酮治疗的患者中头晕更频繁出现（p < 0.001）。
丁螺环酮在GAD儿科患者中耐受性良好，尽管两项随机对照试验检测小效应量（科恩d < 0.15）的能力不足。最后，贝叶斯方法可能有助于重新审视已放弃临床试验的数据。
