回顾急性偏头痛临床试验文献,并总结此类试验中使用的终点和结果。
系统的文献综述,遵循预先指定的(但未注册的)协议,以遵守系统审查和荟萃分析的首选报告项目的建议,目的是了解急性偏头痛临床试验中使用的终点和结局。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。最终数据库搜索于2019年10月28日进行。根据既定的纳入和排除标准对已确定的出版物进行审查,以确定合格性。与一般试验设计特性相关的数据,样本特征,每个出版物中报告的结局和终点均从符合条件的出版物中提取.设计特征的描述性摘要,样本特征,构建了跨出版物使用的终点和结局。结果分为四大类:(a)疼痛相关结果(疼痛缓解,痛苦的自由,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,和(C)响应者定义(例如,减少50%)。这篇综述的重点是最近(1998年或以后)的随机和盲化出版物的一部分,这些出版物评估了药物或医疗设备。
在通过初始搜索和参考部分审查发现的1567种出版物中,705符合标准,并纳入数据提取。提取的描述性变量的评分者间一致kappas的平均kappa估计值为0.86。最近,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,从疼痛缓解或自由,免于或缓解偏头痛相关症状,使用急性或抢救药物,和其他各种PROM,包括满意度和生活质量的衡量标准。在最近的随机和盲文子集中,大多数文章检查≥1疼痛相关结局(430/451,95.3%).在检查疼痛的出版物中,最常用的结果是疼痛缓解(310/430,72.1%),疼痛自由度(279/430,64.9%),和头痛复发(202/43,051,47.0%)或抢救药物使用(278/430,64.9%)。相关症状如恶心,畏光,与大多数烦人的相关症状(16/451,3.5%)相比,恐惧症的测量频率更高(299/451,66.3%),因为它是监管指导的新补充。超过三分之一的合格出版物检查了残疾/障碍(186/451,41.2%)或≥1次PROM(159/451,35.3%)。使用的端点的定义(例如,从基线变化,固定时间点比较,根据各种各样的“响应者定义”)对治疗的“响应者”分类也在不同的出版物中大不相同。
急性偏头痛临床试验在使用的结局和终点方面表现出很大的变异性,除了不同试验间结局和终点使用方式的差异外.试验中有一些共同的元素与国际头痛协会的指导一致,食品药品监督管理局和其他监管机构(例如,评估疼痛和相关症状,2小时后处理)。急性偏头痛临床试验设计的其他方面没有遵循指导。例如,用于测量结构的多项目PROM(例如,秤)很少使用,疼痛相关结果的使用不一致,一些相关的症状评估是特殊的,主要终点的评估时间是可变的。以患者为中心和统计上稳健的急性偏头痛临床试验的一组核心结果和终点的开发可以改善个体试验的进行。促进交叉试验比较,并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.