Leidy Nancy K, Murray Lindsey T, Monz Brigitta U, Nelsen Linda, Goldman Mitchell, Jones Paul W, Dansie Elizabeth J, Sethi Sanjay
Evidera, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, 20814, USA.
Formerly Boehringer Ingelheim GmbH, Ingelheim, Germany.
Respir Res. 2014 Oct 7;15(1):124. doi: 10.1186/s12931-014-0124-z.
Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT - Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.
This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset.
In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman's rho; p < 0.01, all comparisons listed here): FEV1% predicted (-0.19, -0.14, -0.15); St. George's Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (-0.30, -0.14) and incremental shuttle walk (ISWT) (-0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.
Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.
MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516.
症状缓解是慢性阻塞性肺疾病（COPD）患者的重要治疗目标。迄今为止，尚无根据美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）指南开发并经过科学验证的用于评估临床试验中呼吸道症状的日记。EXACT-呼吸道症状（E-RS）量表是一种患者报告结局（PRO）指标，旨在满足这一需求。E-RS采用了现有且经过验证的14项EXACT中的11项呼吸道症状条目，该量表用于测量急性加重症状。E-RS总分量化呼吸道症状的严重程度，3个领域分别评估呼吸困难、咳嗽和咳痰以及胸部症状。
本研究在3项对照试验中考察了E-RS的性能，这些试验具有共同和独特的验证变量：一项为期6个月（N = 235，美国），两项为期3个月（N = 749；N = 597；国际）。受试者将E-RS作为每日电子日记的一部分来完成。在每个数据集中进行了信度、效度和反应度测试。
在每项研究中，RS总分在稳定患者中具有内部一致性（Cronbach α）（分别为0.88、0.92、0.92）且具有可重复性（组内相关性）（间隔2天：0.91；间隔7天：0.71、0.74）。RS总分与以下标准变量显著相关（Spearman秩相关系数；p < 0.01，此处列出所有比较）：预测的第一秒用力呼气容积（FEV1%）（-0.19、-0.14、-0.15）；圣乔治呼吸问卷（SGRQ）（0.65、0.52、0.51）；呼吸困难、咳嗽和咳痰量表（BCSS）（0.89、0.89）；改良医学研究委员会呼吸困难量表（mMRC）（0.40）；急救药物使用情况（0.43、0.42）；功能表现量表简表（FPI-SF）（0.43）；6分钟步行距离（6-MWT）（-0.30、-0.14）和递增往返步行试验（ISWT）（-0.18）。这些变量与RS-呼吸困难、RS-咳嗽和咳痰、RS-胸部症状评分之间的相关性支持了分量表的效度。RS总分、RS-呼吸困难和RS-胸部症状区分了mMRC呼吸困难严重程度水平（p < 0.0001）。RS总分和领域评分区分了未使用急救药物和使用3次或更多次急救药物的受试者（p < 0.0001）。还显示了对健康状况变化（SGRQ）、症状（BCSS）和运动能力（6MWT、ISWT）的敏感性，并提出了基于标准和基于分布的方法的反应者定义。
结果表明，E-RS是一种可靠、有效且具有反应度的COPD呼吸道症状测量指标，适用于自然史研究和临床试验。
MPEX：NCT00739648；AZ1：NCT00949975；AZ 2：NCT01023516。
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