Division of Epilepsy and EEG, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Road - 4036, Boston, MA, 02115, USA.
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
J Neurol. 2018 Sep;265(9):2137-2142. doi: 10.1007/s00415-018-8971-z. Epub 2018 Jul 12.
We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti-epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of developing the side effects was calculated for each drug load, and the presence of a dose-response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Keeping in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability.
我们旨在调查用于描述认知和疲劳相关副作用的术语及其在抗癫痫药物（AED）附加临床试验中的流行程度。我们从公开的 FDA 文件和已发表的文献中提取数据。然后将目标药物剂量计算为药物负荷并分为三类（低、中、高）。计算了每种药物负荷下出现副作用的比值比，并评估了剂量反应效应的存在。我们发现，试验中使用的认知术语非常多样，关于停药率的数据有限。认知副作用的安慰剂率范围为 0 至 10.6%，而疲劳的安慰剂率范围为 2.5 至 37.7%。考虑到可变的安慰剂率和术语，除了认知副作用的 brivaracetam 和 zonisamide 以及疲劳副作用的 tiagabine、topiramate 和 zonisamide 外，大多数 AED 都表现出明显的剂量反应效应和显著的比值比在高剂量下。由于这些副作用与生活质量密切相关且具有临床意义，新的试验应公开提供这些副作用的流行率和停药率相关数据。鉴于明确的剂量反应效应，医生应考虑降低药物负荷并调整剂量以提高耐受性。
