title: Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516.
authors.affiliation: Evidera, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, 20814, USA. nancy.leidy@evidera.com.
authors.forename: Nancy K
authors.initials: NK
authors.lastname: Leidy
authors.affiliation: Evidera, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, 20814, USA. lindsey.murray@evidera.com.
authors.forename: Lindsey T
authors.initials: LT
authors.lastname: Murray
authors.affiliation: Formerly Boehringer Ingelheim GmbH, Ingelheim, Germany. lbmonz@t-online.de.
authors.forename: Brigitta U
authors.initials: BU
authors.lastname: Monz
authors.affiliation: Merck, Sharp & Dohme, Corp, Whitehouse Station, NJ, USA. linda.m.nelsen@gsk.com.
authors.forename: Linda
authors.initials: L
authors.lastname: Nelsen
authors.affiliation: AstraZeneca, Wilmington, DE, USA. mitchell.goldman@astrazeneca.com.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldman
authors.affiliation: St. George's, University of London, London, UK. pjones@sgul.ac.uk.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Jones
authors.affiliation: Evidera, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, 20814, USA. elizabeth.dansie@evidera.com.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Dansie
authors.affiliation: University of Buffalo, Buffalo, NY, USA. ssethi@buffalo.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
mesh_terms: D000368:Aged; D003371:Cough / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D004311:Double-Blind Method; D004417:Dyspnea / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D006304:Health Status; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D015203:Reproducibility of Results; D012720:Severity of Illness Index; D013183:Sputum; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome