Background

Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients.

Methods

In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations.

Findings

At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size.

Interpretation

COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

中文翻译：

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COPDCompEx：COPD急性发作的新型复合终点，可加快临床开发速度

背景

在临床试验中，中度和重度慢性阻塞性肺疾病恶化的频率是一个重要的终点，但是当对其进行评估时，会使它们又大又长。我们旨在开发一种复合终点（COPDCompEx），该终点可以预测对急性发作的治疗效果，从而能够设计出需要更少患者的更短的早期临床试验。

方法

在此事后分析中，使用了20个随机对照试验的数据来开发和测试COPDCompEx。针对峰值呼气流量，缓解药物的使用和症状，针对预定义的阈值测试了日记事件。COPDCompEx事件定义为首次发生日记事件，中度或重度加重或研究辍学。比较COPDCompEx与中度和重度急性加重期间事件发生频率，治疗效果和未来试验样本量的比率。

发现

在3个月时，经历COPDCompEx事件的患者比例比单独发作时增加了3倍以上。所有组件均导致COPDCompEx事件发生率。3个月时的治疗效果在COPDCompEx和急性加重之间非常接近，并且巨大的净功率增加显着减少了所需的样本量。

解释

COPDCompEx可用于预测对慢性阻塞性肺疾病的中度和重度加重的治疗效果。与目前的急性加重研究相比，这可能使设计更短的2期临床试验需要更少的患者，而加重是3期的关键终点。因此，这将允许更有效的决策，同时减轻研究参与者的负担和风险。