Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials

Nancy K Leidy, Lindsey T Murray, Brigitta U Monz, Linda Nelsen, Mitchell Goldman, Paul W Jones, Elizabeth J Dansie, Sanjay Sethi, Nancy K Leidy, Lindsey T Murray, Brigitta U Monz, Linda Nelsen, Mitchell Goldman, Paul W Jones, Elizabeth J Dansie, Sanjay Sethi

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.

Trial registration: MPEX: NCT00739648 ; AZ1: NCT00949975 ; AZ 2: NCT01023516.

Figures

Figure 1
Figure 1
E-RS Scores by Level of Dyspnoea and Rescue Medication Use. A: Level of Dyspnea (mMRC†). †Mpex data only; E-RS mean weekly scores (Day −7 to Day −1); ANCOVA controlling for age, co-morbidity, and baseline FEV1. ***p < 0.001; ****p < 0.0001 from global test of differences between levels. Abbreviations: ANCOVA = analysis of covariance; E-RS = Exacerbations of Chronic Pulmonary Disease Tool – Respiratory Symptoms; FEV1 = forced expiratory volume in 1 second; mMRC = modified Medical Research Council dyspnoea scale. B: Rescue Medication Use†. †Results for AZ 1 data shown; similar results were found in AZ 2 data; E-RS and rescue medication use are mean weekly values (Day −7 to Day −1); Students t-test. ****p < 0.0001. Abbreviations: AZ = AstraZeneca; E-RS = Exacerbations of Chronic Pulmonary Disease Tool – Respiratory Symptoms.
Figure 2
Figure 2
E-RS Score Improvements by Health Status, Respiratory Symptom, or Exercise Capacity Improvement at 3 Months. A: RS-Total. *Data from one subject with an extreme positive (worse) E-RS Cough & Sputum score (8 SD) removed from the analysis. Abbreviations: 6MWT = 6-minute walk test; AZ = AstraZeneca; BCSS = Breathlessness, Cough and Sputum Scale; ISWT = Incremental Shuttle Walk Test; SGRQ = St. George’s Respiratory Questionnaire. B: RS-Breathlessness. *Data from one subject with an extreme positive (worse) E-RS Cough & Sputum score (8 SD) removed from the analysis. Abbreviations: 6MWT = 6-minute walk test; AZ = AstraZeneca; BCSS = Breathlessness, Cough and Sputum Scale; ISWT = Incremental Shuttle Walk Test; SGRQ = St. George’s Respiratory Questionnaire. C: RS-Cough and Sputum. *Data from one subject with an extreme positive (worse) E-RS Cough & Sputum score (8 SD) removed from the analysis. Abbreviations: 6MWT = 6-minute walk test; AZ = AstraZeneca; BCSS = Breathlessness, Cough and Sputum Scale; ISWT = Incremental Shuttle Walk Test; SGRQ = St. George’s Respiratory Questionnaire. D: RS-Chest Symptoms. *Data from one subject with an extreme positive (worse) E-RS Cough & Sputum score (8 SD) removed from the analysis. Abbreviations: 6MWT = 6-minute walk test; AZ = AstraZeneca; BCSS = Breathlessness, Cough and Sputum Scale; ISWT = Incremental Shuttle Walk Test; SGRQ = St. George’s Respiratory Questionnaire.

References

    1. Calverley PM, Georgopopoulos D. Chronic obstructive pulmonary disease: symptoms and signs. Eur Respir Mon. 2006;38:7–23.
    1. Celli BR, MacNee W, ATS ERS Task Force Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932–946. doi: 10.1183/09031936.04.00014304.
    1. Chong-Chen LU. Bronchodilator therapy for chronic obstructive pulmonary disease. Respirology. 1997;2:317–322. doi: 10.1111/j.1440-1843.1997.tb00096.x.
    1. Food and Drug Administration Draft guidance for industry on chronic obstructive pulmonary disease: developing drugs for treatment; availability. Fed Regist. 2007;72:63618.
    1. Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management, and Prevention of COPD. []
    1. Siafakas NM, Celli B. Overall management of stable chronic obstructive pulmonary disease. Eur Respir Mon. 2006;38:258–265.
    1. Viegi G, Pistelli F, Sherrill DL, Maio S, Baldacci S, Carrozzi L. Definition, epidemiology and natural history of COPD. Eur Respir J. 2007;30:993–1013. doi: 10.1183/09031936.00082507.
    1. Cooper CB. The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function. Am J Med. 2006;119(Suppl 1):21–31. doi: 10.1016/j.amjmed.2006.08.004.
    1. Ries AL. Impact of chronic obstructive pulmonary disease on quality of life: the role of dyspnea. Am J Med. 2006;119(Suppl 1):12–20. doi: 10.1016/j.amjmed.2006.08.003.
    1. Tsiligianni I, Kocks J, Tzanakis N, Siafakas N, van der Molen T. Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations. Prim Care Respir J. 2011;20:257–268. doi: 10.4104/pcrj.2011.00029.
    1. Leidy NK, Wilcox TK, Jones PW, Murray L, Winnette R, Howard K, Petrillo J, Powers J, Sethi S, EXACT-PRO Study Group Development of the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): a patient-reported outcome (PRO) measure. Value Health. 2010;13:965–975. doi: 10.1111/j.1524-4733.2010.00772.x.
    1. Jones PW, Chen WH, Wilcox TK, Sethi S, Leidy NK, EXACT-PRO Study Group Characterizing and quantifying the symptomatic features of COPD exacerbations. Chest. 2011;139:1388–1394. doi: 10.1378/chest.10-1240.
    1. Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S, EXACT-PRO Study Group Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary. Am J Respir Crit Care Med. 2011;183:323–329. doi: 10.1164/rccm.201005-0762OC.
    1. Leidy NK, Murray LT, Jones P, Sethi S. Performance of the EXAcerbations of chronic pulmonary disease tool patient-reported outcome measure in three clinical trials of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11:316–325. doi: 10.1513/AnnalsATS.201309-305OC.
    1. Leidy NK, Murray LT. Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS. COPD. 2013;10:393–398. doi: 10.3109/15412555.2013.795423.
    1. Food and Drug Administration Draft guidance for industry on qualification of exacerbations of chronic pulmonary disease tool for measurement of symptoms of acute bacterial exacerbations of chronic bronchitis in patients with chronic obstructive pulmonary disease. Fed Regist. 2014;79:1873–1874.
    1. Food and Drug Administration Guidance for industry on patient-reported outcome measures: use in medical product development to support labeling claims. Fed Regist. 2009;74:65132–65133.
    1. Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity–establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO good research practices task force report: part 1–eliciting concepts for a new PRO instrument. Value Health. 2011;14:967–977. doi: 10.1016/j.jval.2011.06.014.
    1. Patrick DL, Burke LB, Gwaltney CJ, Leidy NK, Martin ML, Molsen E, Ring L. Content validity–establishing and reporting the evidence in newly developed patient-reported outcomes (PRO) instruments for medical product evaluation: ISPOR PRO Good Research Practices Task Force report: part 2–assessing respondent understanding. Value Health. 2011;14:978–988. doi: 10.1016/j.jval.2011.06.013.
    1. Leidy NK, Sexton CC, Jones PW, Notte SM, Monz BU, Nelsen L, Goldman M, Murray LT, Sethi S. Measuring respiratory symptoms in clinical trials of COPD: reliability and validity of a daily diary. Thorax. 2014;69:424–430. doi: 10.1136/thoraxjnl-2013-204428.
    1. Vogelmeier C, Aquino TO, O'Brien CD, Perrett J, Gunawardena KA. A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium. COPD. 2012;9:111–120. doi: 10.3109/15412555.2011.641803.
    1. Kuna P, Jenkins M, O'Brien CD, Fahy WA. AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD. Respir Med. 2012;106:531–539. doi: 10.1016/j.rmed.2011.10.020.
    1. Leidy NK, Schmier JK, Jones MK, Lloyd J, Rocchiccioli K. Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. Respir Med. 2003;97(Suppl A):S59–S70. doi: 10.1016/S0954-6111(03)80016-1.
    1. Leidy NK, Rennard SI, Schmier J, Jones MK, Goldman M. The breathlessness, cough, and sputum scale: the development of empirically based guidelines for interpretation. Chest. 2003;124:2182–2191. doi: 10.1378/chest.124.6.2182.
    1. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145:1321–1327. doi: 10.1164/ajrccm/145.6.1321.
    1. Fletcher CM, Elmes PC, Fairbairn AS, Wood CH. The significance of respiratory symptoms and the diagnosis of chronic bronchitis in a working population. Br Med J. 1959;2:257–266. doi: 10.1136/bmj.2.5147.257.
    1. Leidy NK, Knebel A. Clinical validation of the Functional Performance Inventory in patients with COPD. Respir Care. 1999;44:932–939.
    1. Leidy NK, Hamilton A, Becker K. Assessing patient report of function: content validity of the Functional Performance Inventory-Short Form (FPI-SF) in patients with chronic obstructive pulmonary disease (COPD) Int J Chron Obstruct Pulmon Dis. 2012;7:543–554. doi: 10.2147/COPD.S32032.
    1. Jones PW. St. George’s Respiratory Questionnaire: MCID. COPD. 2005;2:75–79. doi: 10.1081/COPD-200050513.
    1. Puhan MA, Chandra D, Mosenifar Z, Ries A, Make B, Hansel NN, Wise RA, Sciurba F, National Emphysema Treatment Trial Research Group The minimal important difference of exercise tests in severe COPD. Eur Respir J. 2011;37:784–790. doi: 10.1183/09031936.00063810.
    1. Singh SJ, Jones PW, Evans R, Morgan MD. Minimum clinically important improvement for the incremental shuttle walking test. Thorax. 2008;63:775–777. doi: 10.1136/thx.2007.081208.
    1. Hays RD, Anderson RT, Revicki DA. Assessing reliability and validity of measurement in clinical trials. In: Staquet MJ, Hays RD, editors. Quality of Life Assessment in Clinical Trials: Methods and Practice. New York: Oxford University Press; 1998. pp. 169–182.
    1. Nunnally JC, Bernstein IH. Psychometric Theory. 3. New York: McGraw-Hill; 1994.
    1. Chinn S. Statistics in respiratory medicine. 2. Repeatability and method comparison. Thorax. 1991;46:454–456. doi: 10.1136/thx.46.6.454.
    1. PM F, Hays R, editors. Assessing Quality of Life in Clinical Trials: Methods and Practice. 2. New York: Oxford University Press; 2005.
    1. Rutten-van Molken M, Roos B, Van Noord JA. An empirical comparison of the St George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ) in a clinical trial setting. Thorax. 1999;54:995–1003. doi: 10.1136/thx.54.11.995.
    1. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. Eur Respir J. 2009;34:648–654. doi: 10.1183/09031936.00102509.
    1. Gupta N, Pinto LM, Morogan A, Bourbeau J: The COPD assessment test: a systematic review.Eur Respir J 2014. in press.
    1. Johnston N, O'Byrne P, Kolb M. The promise of electronic data capture in respiratory medicine. Eur Respir J. 2011;37:228–230. doi: 10.1183/09031936.00141310.
    1. Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA. Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med. 2014;189(3):250–255. doi: 10.1164/rccm.201310-1863PP.
    1. Beier J, Kirsten AM, Mroz R, Segarra R, Chuecos F, Caracta C, Gil EG. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled Phase IIIb study. COPD. 2013;10:511–522. doi: 10.3109/15412555.2013.814626.

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