Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA.
StatMind Statistical and Mathematical Modelling, Innovation and Design AB, Lund, Sweden.
Lancet Respir Med. 2017 Jul;5(7):577-590. doi: 10.1016/S2213-2600(17)30218-7. Epub 2017 Jun 2.
Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations.
Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35-53 years, 59-69% were female, and had a mean FEV percentage of predicted normal of 63-84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations.
CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2·8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1·01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed.
CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations.
AstraZeneca.
严重哮喘发作的发生是评估哮喘管理的基石，但严重哮喘发作是罕见事件。因此，评估药物对发作疗效的试验是在临床开发计划的后期进行的。我们旨在建立一个捕捉临床相关恶化的终点（日记事件），当与严重发作相结合时，形成一个复合结局（CompEx）。CompEx 需要强烈反映与经过严重发作验证的结局相关的结果，以便设计持续时间更短且纳入患者人数少于评估严重发作的试验的临床试验。
使用来自 12 项为期 6 个月或 12 个月的哮喘试验的数据，并进行标准化的发作和日记卡变量收集，构建和测试 CompEx。研究人群的平均年龄为 35-53 岁，59-69%为女性，平均 FEV%预测正常为 63-84%。使用五项试验的数据，我们基于呼气峰流速 (P)、缓解药物使用 (R)、症状 (S)、觉醒 (A) 和从基线变化的阈值以及斜率建立了一系列日记事件，以评估趋势。在开发阶段，我们评估了不同的变量组合和恶化标准，以选择最稳健的算法来定义用于复合结局的日记事件。我们定义了一个复合结局 CompEx，即首次出现日记事件或严重发作。我们通过比较 CompEx 与严重发作的发作频率、治疗效果（风险比；HR）和未来试验所需的样本量，评估 CompEx 在七项试验中的性能。
CompEx（基于 PRS）是满足我们两个标准的最佳算法。当在 3 个月时进行删失时，CompEx 的事件发生次数是严重发作的 2.8 倍，同时保留了严重发作中观察到的治疗效果（CompEx 与严重发作平均 HR 1.01）。增加的事件数量，加上持续的治疗效果，导致功效大幅提高，在严重发作药物试验中，患者人数减少了 67%。在测试的七个比较中有六个，CompEx 至少减少了 50%的样本量需求。对独立测试人群的验证证实了 CompEx 增加事件频率、保留治疗效果和减少所需患者人数的能力。
CompEx 是一种用于评估新哮喘疗法的复合结局。CompEx 允许设计持续时间更短且纳入患者人数少于严重发作研究的试验，同时保持与严重发作相比显示治疗效果的能力。
阿斯利康。
