Systematic review of outcomes and endpoints in acute migraine clinical trials.
Systematic review of outcomes and endpoints in acute migraine clinical trials.
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作者：
Houts CR;McGinley JS;Nishida TK;Buse DC;Wirth RJ;Dodick DW;Goadsby PJ;Lipton RB
回顾急性偏头痛临床试验文献，并对这些试验的终点和结果进行总结。为了了解急性偏头痛临床试验的终点和结果，我们按照预先指定的（但未注册的）方案进行了系统性文献综述，该方案遵循了系统评价和Meta分析的首选报告项目的建议。在PubMed中搜索预定义的术语，以定位评估急性偏头痛治疗的临床试验。最终的数据库检索于2019年10月28日进行。根据既定的纳入和排除标准对确定的出版物进行审查，以确定其资格。与一般试验设计特征、样本特征、结果和终点相关的数据从符合条件的出版物中提取。构建了设计特征、样本特征以及跨出版物采用的终点和结果的描述性摘要。结果分为四大类：(a)疼痛相关结果（疼痛缓解、疼痛缓解等），(b)相关症状（恶心、畏光等），(c)残疾/损伤/影响，(d)患者报告的结果测量（PROMs、一般健康状况和偏头痛/头痛特异性）。终点类型分为三大类：(a)基线变化，(b)固定时间点，(c)应答者定义（例如，减少50%）。本综述的重点是最近（1998年或以后）随机和盲法出版物评价药物或医疗器械的子集。在通过初步检索和参考文献部分审查找到的1567份出版物中，有705份符合标准并被纳入数据提取。所提取的描述性变量间一致性kappa的平均kappa估计值为0.86。最近的随机和盲法药物和医疗器械文章子集包括451篇出版物（451/705,63.9%）。不同试验的结果和终点差异很大，包括疼痛缓解或缓解，偏头痛相关症状的缓解或缓解，急性或抢救药物的使用，以及各种其他PROMs，包括满意度和生活质量的测量。在最近的随机和盲法研究中，大多数研究检查了≥1个疼痛相关结局（430/451,95.3%）。在检查疼痛的出版物中，最常使用的结果是疼痛缓解（310/430,72.1%）、疼痛缓解（279/430,64.9%）和头痛复发（202/43,051,47.0%）或救援药物使用（278/430,64.9%）。与大多数令人烦恼的相关症状（16/451,3.5%）相比，恶心、畏光和声音恐惧症等相关症状的测量频率更高（299/451,66.3%），因为这是监管指导的新内容。超过三分之一的合格出版物检查了残疾/损伤（186/451,41.2%）或≥1个PROM（159/451, 35.3%）。所用终点的定义（例如，从基线变化、固定时间点比较、根据各种“应答者定义”对“应答者”的分类）在不同出版物之间也存在很大差异。急性偏头痛临床试验在使用的结果和终点上表现出大量的可变性，除了在不同试验之间如何使用结果和终点的可变性之外。所有试验都有一些共同的要素，这些要素与国际头痛学会、食品和药物管理局和其他监管机构的指导相一致（例如，评估疼痛和相关症状，治疗后2小时）。急性偏头痛其他方面的临床试验设计没有遵循指导。例如，用于测量结构（如量表）的多项目PROMs很少被使用，疼痛相关结果的使用是不一致的，一些相关症状评估是特殊的，主要终点评估的时间是可变的。急性偏头痛临床试验的核心结果和终点的发展，以患者为中心，在统计上是稳健的，可以改善个体试验的进行，促进交叉试验的比较，更好地支持医疗保健专业人员和患者的知情治疗决策。
To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain‐related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient‐reported outcome measures (PROMs, general health and migraine/headache‐specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter‐rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine‐associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain‐related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one‐third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial‐to‐trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2‐hour post‐treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi‐item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain‐related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient‐centered and statistically robust could improve the conduct of individual trials, facilitate cross‐trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.
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DOI：
10.1016/s1474-4422(18)30387-9
发表时间：
2018-12
期刊：
The Lancet. Neurology
影响因子：
--
作者：
GBD 2016 Meningitis Collaborators
通讯作者：
GBD 2016 Meningitis Collaborators
影响因子：
9.9
作者：
Lipton, R. B.;Bigal, M. E.;Stewart, W. F.
通讯作者：
Stewart, W. F.
影响因子：
4.9
作者：
Tfelt-Hansen, Peer;Pascual, Julio;Schwedt, Todd
通讯作者：
Schwedt, Todd
影响因子：
4.9
作者：
Diener, Hans-Christoph;Tassorelli, Cristina;Mandrekar, Jay
通讯作者：
Mandrekar, Jay
影响因子：
5
作者：
Buse, Dawn C.;Loder, Elizabeth W.;Lipton, Richard B.
通讯作者：
Lipton, Richard B.