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Abstract
Rationale: The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) is a patient-reported outcome measure to standardize the symptomatic assessment of chronic obstructive pulmonary disease exacerbations, including reported and unreported events. The instrument has been validated in a short-term study of patients with acute exacerbation and stable disease; its performance in longer-term studies has not been assessed.
Objectives: To test the EXACT’s performance in three randomized controlled trials and describe the relationship between resource-defined medically treated exacerbations (MTEs) and symptom (EXACT)-defined events.
Methods: Prespecified secondary analyses of data from phase II randomized controlled trials testing new drugs for the management of chronic obstructive pulmonary disease: one 6-month trial (United States) (n = 235) and two 3-month, multinational trials (AZ 1 [n = 749], AZ 2 [n = 597]). In each case, the experimental drugs were found to be ineffective, permitting assessment of the EXACT’s performance in three independent studies of moderate to severe high-risk patients on maintenance therapies.
Measurements and Main Results: The mean age of subjects was 62 to 64 years; 48 to 76% were male. Mean FEV1 % predicted was 42 to 59%. EXACT scores exhibited internal consistency (Cronbach’s α ≥ 0.90), reproducibility (intraclass correlation ≥ 0.70), correlation with St. George’s Respiratory Questionnaire (Spearman rho [rs] = 0.62, 0.46, 0.46 in the three trials; P < 0.001), and Breathlessness Cough and Sputum Scale (AZ 1, rs = 0.83; AZ 2, rs = 0.83; P < 0.001). EXACT-defined events had a high correspondence with alternative indicators of worsening (94, 88, and 93%). In each trial, unreported events were similar in severity (mean EXACT score, 56, 57, 61 vs. 53, 54 [P < 0.05], 57 [P < 0.05], respectively; 100-point scale) and longer (median, 9, 8, 7 vs. 8, 7 [P < 0.01], 6 days, respectively) than moderate MTEs.
Conclusions: Data generated through the EXACT offers insight into the symptomatic nature of MTEs and the frequency, severity, and duration of unreported symptom-defined events.
Clinical trials registered with www.clinicaltrials.gov (MPEX: NCT00739648; AZ 1: NCT00949975; AZ 2: NCT01023516).
Exacerbations of chronic obstructive pulmonary disease (COPD) are an acute, sustained worsening of the patient’s underlying condition beyond normal day-to-day variability, leading to a change in treatment (1). They are a major cause of morbidity and mortality (1–7) and a significant burden on health-care systems worldwide (1, 8, 9). Rates vary across the COPD population, with some patients more prone to recurrent events (1, 3, 10, 11).
Until recently there has been no empirically derived definition or description of an exacerbation. Historically, exacerbations have been defined by health-care resource use (i.e., clinic or emergency visits with oral steroid or antibiotic treatment [moderate], or hospitalization [severe]) (12, 13). However, there are limitations to this definition. Clinic visits are initiated by patients triggered by various factors, including their assessment of the episode, provider relationship, family influences, and cost. With as many as 50 to 70% of exacerbations unreported in previous studies (14–16), resource-based definitions seriously underestimate exacerbation frequency. In addition, there is no standardized method for clinical diagnosis and treatment. Decisions are based on clinician training, experience, treatment preferences, experience with the patient, and health-care setting, among others. Finally, many studies rely on patient recall of medically treated exacerbations (MTEs) during periodic study visits.
A symptom-based method of prospectively assessing exacerbations can address many of these limitations. Anthonisen and colleagues (17) was one of the first studies to use a symptom-based algorithm to characterize events associated with clinic visits for an antibiotic trial. Seemungal and colleagues (15) extended this definition, using a daily diary to document reported and unreported events (3, 18, 19). Since that time, various methods have been used to document symptomatic change with MTEs in clinical trials and/or identify unreported events. Diversity in content and structure of these methods has made cross-study comparison difficult. Furthermore, none of these patient-reported outcome measures have been developed using procedures consistent with U.S. Food and Drug Administration and European Medicines Agency guidelines (20, 21), making them unsuitable for use as a primary or secondary endpoint in drug development trials (22, 23).
The EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) is a patient-reported outcome diary designed to count and characterize symptom-defined exacerbations (frequency, severity, duration). It was developed using rigorous qualitative and quantitative methods, with the participation of experts and unrestricted funds provided through a multisponsor consortium (24–29). The first validation study provided evidence of score reliability, validity, and sensitivity to change in patients enrolled during an acute event and followed for 30 days, with a sample of stable patients followed for 7 days serving as a control group (24, 27). The EXACT’s performance in longer-term studies and clinical trials has not been assessed. Of particular interest was the consistency in score reliability and validity estimates across different studies and the performance of the measure over time in patients enrolled during a clinically stable state and followed over one or more exacerbation.
This study examined the performance of the EXACT in three randomized controlled trials, testing score reliability and validity and describing frequency, severity, and duration of exacerbations using symptom (EXACT)-based and resource use–based methods.
Prespecified secondary analyses were performed on data from three phase II multicenter, randomized, double-blind, placebo-controlled trials in which participants were enrolled in a stable state and followed over time. The first dataset (Mpex) was a 6-month U.S. trial testing MP-376 (levofloxacin) inhalation solution administered for 5 days every 28 days to prevent exacerbations in high-risk patients with COPD (protocol MPEX-302; ClinicalTrials.gov identifier NCT00739648). Maintenance therapies were based on clinician discretion. Relevant inclusion criteria were: age 40 years or older; post-bronchodilator FEV1 less than or equal to 70% predicted and FEV1/FVC less than or equal to 0.7; two or more documented MTEs in the prior 12 months; stable on long-acting bronchodilators and/or inhaled or systemic steroids during the 30-day prebaseline period; and mucopurulent sputum on most days, even when exacerbation-free.
Two datasets were from 12-week, parallel-group, multinational trials testing AZD9668 (a neutrophil elastase inhibitor) in patients with COPD. AZ 1 was dose ranging, with patients standardized to a baseline treatment of tiotropium (protocol D0520C00012; ClinicalTrials.gov identifier NCT00949975) (30). AZ 2 tested one dose against placebo, with each patient also receiving budesonide/formoterol (protocol D0520C00020; ClinicalTrials.gov identifier NCT01023516) (31). Relevant inclusion criteria were: age 40 to 80 years; FEV1 % predicted, 40 to 80% (AZ 1) or 30 to 80% (AZ 2); one or more MTEs the prior year; Breathlessness, Cough, and Sputum Scale (BCSS) (32, 33) score greater than or equal to 2 per day for 7 of 14 days before Visit 2; and no health-care resource use visits or treatment for exacerbation for at least 4 weeks before randomization.
According to study sponsors, trial procedures adhered to the Declaration of Helsinki and the participating institution’s institutional review board approved the protocol(s). In each trial, the experimental drug was found to be ineffective, permitting assessment of the EXACT’s performance in three independent studies of moderate to severe high-risk patients on maintenance therapies.
In all trials, participants completed an eDiary each evening before bedtime that included the 14-item EXACT and trial-specific assessments. The EXACT includes questions on breathlessness, cough, sputum, chest congestion, sleep disturbance, feeling weak or tired, and feeling worried or concerned. Interval level scores range from 0 to 100, with higher scores indicating a worse COPD health state (24). (Scoring rules are provided in the online supplement.) In the Mpex trial diary, participants also recorded daily global health ratings, clinic contact or visit, and rescue medication use. The AZ trial eDiaries included the three-item BCSS, rescue medication use, eFEV1, and ePEF (peak expiratory flow).
During clinic visits, patients completed the St. George’s Respiratory Questionnaire (SGRQ) (34, 35).
Spirometry was performed at enrollment and each subsequent clinic visit.
Each trial identified and defined MTEs as moderate (clinic or emergency room visits with antibiotic and/or systemic corticosteroid treatment) or severe (hospitalization for exacerbation of COPD), with data provided by patients during study visits. Duration was defined by the longer of pharmacologic treatment or hospital days. Symptom severity was defined as the highest (worst) EXACT score observed during the MTE.
Symptom-based exacerbations were defined as a sustained worsening of EXACT daily scores above baseline (≥ 9 points) for 3 consecutive days or 12 or more points for 2 consecutive days (27). Recovery was defined by an improvement of at least 9 points from the maximum value during the event, sustained for 7 days using a 3-day rolling average, with the first day designated the day of recovery. Duration was the number of days, onset to recovery; severity was the highest (worst) recorded score during the event (see online supplement).
A statistical analysis plan was developed for each dataset before analysis. Differences in trial duration, settings, and criterion variables precluded cross-study analyses or data pooling. SAS/STAT software version 9.2 of the SAS System for PC (SAS Institute, Cary, NC) was used.
Tests of EXACT score reliability included internal consistency and reproducibility. Cronbach coefficient α and the person-separation index were used to estimate internal consistency, with the latter offering a more precise method of determining reliability of scores based on Rasch scoring logits. For both parameters, values can range from 0 to 1.0, with higher estimates indicating a more reliable (precise) instrument. Score reproducibility was assessed during the stable run-in period, examining score consistency from Day −7 to Day −1, with the understanding that some variability would be present due to the day-to-day variability of COPD. In the Mpex study, the available data permitted a test of reproducibility over two consecutive days when patients reported their lung condition was unchanged. For each reproducibility analysis, the intraclass correlation coefficient was computed, complemented by an examination of mean differences between the two observations.
Evaluation of validity included tests of the relationship between EXACT scores and three criterion variables: SGRQ, a measure of health status; BCSS, a respiratory symptom measure; and FEV1 % predicted. Spearman rho was used, hypothesizing that correlations between the EXACT and SGRQ total scores would be moderate (rs ≥ 0.40–0.60), with weaker moderate correlations with SGRQ subscale scores (rs, 0.30–0.50). The relationship between EXACT and BCSS scores was expected to be strong (rs > 0.60–0.80). Because the EXACT quantifies the severity of symptoms characteristic of COPD exacerbations, and the relationship between symptoms and pulmonary function is known to be weak, the correlation between the EXACT and FEV1 was expected to be low (rs < 0.20).
Validity was also assessed by examining the relationship between first symptom (EXACT)-defined events and other indicators of patient worsening recorded in the diary within 3 days of event onset. The same relationships were examined for first MTE and compared using the Chi-square test. Patterns and changes in EXACT scores around MTEs were examined, including change in group-level scores around MTEs and the frequency with which MTEs were accompanied by an EXACT-defined event within a 7-day window. Because patients vary in their decisions to seek care, and clinicians vary in their decisions to treat, a perfect correspondence between symptom-defined events and MTEs was not expected.
Descriptive statistics were used to present parameter estimates for frequency, severity, and duration of MTEs and symptom (EXACT)-defined events in each trial. Exacerbation rates were calculated using a negative binomial regression model. Time to first event is presented as a survival curve. Severity and duration of moderate MTEs and unreported symptom (EXACT)-defined events were compared using Student t test and Wilcoxon rank sum tests. The extent to which duration of moderate MTEs differed by definition of event duration (treatment-based versus symptom-based) was tested using Wilcoxon rank sum test. Comparisons with severe MTEs (hospitalizations) were not performed due to small subsample sizes.
Of those randomized, 235 (78%) (Mpex), 749 (89%) (AZ 1), and 597 (97%) (AZ 2) met minimum data requirements for analysis. eDiary compliance rates baseline to final visit were 87, 94, and 97%, respectively. Sample characteristics by study are shown in Table 1.
| Mpex* (N = 235) | AZ 1† (N = 749) | AZ 2‡ (N = 597) | |
|---|---|---|---|
| Age, yr, mean (SD) | 63.7 (8.95) | 62.3 (8.25) | 61.7 (8.27) |
| Sex, male, n (%) | 113 (48.1) | 572 (76.4) | 443 (74.2) |
| Race/ethnicity, n (%) | |||
| White | 214 (91.1) | 536 (71.6) | 592 (99.2) |
| Asian | 2 (0.9) | 212 (28.3) | 0 (0.0) |
| Black/African American | 18 (7.7) | 0 (0.0) | 0 (0.0) |
| Hispanic or Latino | 6 (2.6) | 2 (0.3) | 2 (0.3) |
| Three or more comorbid conditions, n (%) | 235 (100) | 349 (46.6) | 198 (33.2) |
| FEV1, mean (SD) | 1.2 (0.58) | 1.7 (0.49) | 1.6 (0.52) |
| FEV1 % predicted, mean (SD) | 42.2 (18.10) | 58.8 (12.70) | 54.2 (15.36) |
| GOLD stage, n (%)§ | |||
| 0 | 22 (9.4) | 20 (2.7) | 18 (3.0) |
| I | 2 (0.9) | 23 (3.0) | 22 (3.7) |
| II | 55 (23.4) | 503 (67.1) | 300 (50.3) |
| III | 89 (37.9) | 197 (26.3) | 240 (40.2) |
| IV | 66 (28.1) | 5 (0.7) | 16 (2.7) |
| No. of acute exacerbations in past 12 mo, mean (SD) | 2.1 (0.70) | 1.4 (1.05) | 1.2 (0.50) |
| SGRQ total score, mean (SD)ll | 57.4 (16.21) | 52.6 (18.36) | 54.9 (17.14) |
| EXACT baseline score, mean (SD)¶ | 41.8 (9.34) | 42.4 (9.32) | 45.8 (9.39) |
| Range | 17.3–71.1 | 11.5–74.3 | 14.7–92.0 |
| EXACT baseline score, SEM | 0.61 | 0.34 | 0.38 |
| EXACT baseline score intraindividual variability, mean (SD) | 4.0 (2.60) | 3.6 (2.52) | 3.5 (2.44) |
Reliability estimates quantifying EXACT score measurement error in each dataset are shown in Table 2. Internal consistency levels were excellent (≥0.90), indicating a high degree of scale coherence and score precision. Seven-day test–retest values were strong (0.70) to excellent (≥0.75). In the Mpex study, 2-day test–retest was excellent (0.84). In all cases, mean differences between observations were less than 1 point on the 100-point scale.
| Test | Mpex (N = 225–227) | AZ 1 (N = 712–731) | AZ 2 (N = 567–585) |
|---|---|---|---|
| Reliability | |||
| Internal consistency* | 0.90 | 0.94 | 0.94 |
| Test–retest† | 0.70 | 0.75 | 0.77 |
| Mean difference (SD) | −0.9 (8.0) | 0.3 (6.9) | 0.9 (6.9) |
| Validity‡ | |||
| Health status | |||
| SGRQ total (baseline visit) | 0.62§ | 0.46§ | 0.46§ |
| Symptom | 0.37§ | 0.38§ | 0.42§ |
| Activity | 0.54§ | 0.41§ | 0.36§ |
| Impact | 0.58§ | 0.42§ | 0.44§ |
| Respiratory symptoms (Day −1) | |||
| BCSS|| total | — | 0.83§ | 0.83§ |
| Breathlessness | — | 0.74§ | 0.69§ |
| Cough | — | 0.66§ | 0.80§ |
| Sputum | — | 0.68§ | 0.74§ |
| Pulmonary function (baseline visit) | |||
| FEV1 % predicted | −0.14¶ | −0.10¶ | −0.13** |
EXACT scores were significantly correlated with SGRQ and BCSS scores and FEV1 at baseline (Table 2). The correspondence between first EXACT-defined exacerbations and alternative indictors of patient worsening was high (Table 3). In each of the three trials, EXACT events were equivalent or better than MTEs in their association with other indicators of patient worsening.
| Indicator* | ||||
|---|---|---|---|---|
| Mpex† | ||||
| First MTE Event (N = 93) | First Symptom (EXACT)-defined Event (N = 110) | |||
| Patient global rating | 59 (63) | 93 (85) | ||
| Change in dose or medications | 70 (75) | 61 (56) | ||
| Contact with doctor or nurse | 65 (70) | 36 (33) | ||
| Any of the above | 83 (89) | 103 (94) | ||
| AZ 1‡ | AZ 2§ | |||
| First MTE Event (N = 101) | First Symptom (EXACT)-defined Event (N = 241) | First MTE Event (N = 49) | First Symptom (EXACT)-defined Event (N = 173) | |
| BCSS change > 1 point | 44 (44) | 159 (66) | 31 (63) | 122 (71) |
| Decline eFEV1 > 5% | 46 (46) | 126 (52) | 23 (47) | 97 (56) |
| Decline ePEF > 5% | 44 (44) | 137 (57) | 26 (53) | 109 (63) |
| Rescue medication use > 1 puff | 36 (36) | 91 (38) | 11 (22) | 50 (29) |
| Any of the above | 82 (81) | 212 (88) | 40 (82) | 161 (93) |
Frequency, severity, and duration of exacerbations for each event definition are shown in Tables 4 through 6. EXACT events were more frequent than MTEs, and most (70–90%) were unreported. Of the total number of events (MTEs plus unreported symptom-defined), at least half (50–78%) were unreported. Survival curves for MTEs and EXACT events are shown in Figure 1. Patterns of within-patient change in mean EXACT scores with the first MTE and EXACT-defined events are shown in Figure 2.
| Parameter | Mpex, 6 mo (N = 235) | AZ 1, 3 mo (N = 749) | AZ 2, 3 mo (N = 597) |
|---|---|---|---|
| MTEs | |||
| Frequency (total no.)* | 137 | 132 | 59 |
| No. patients with ≥ 1 MTE†, n (%) | 93 (40) | 101 (14) | 49 (8) |
| Range of MTE/person | 1–5 | 1–4 | 1–3 |
| Median time to first MTE, d | 65 | 27 | 44 |
| Rate, pp/py‡ | 1.30 | 0.72 | 0.44 |
| Symptom (EXACT)-defined events | |||
| Frequency (total no.)* | 198 | 320 | 229 |
| No. (%) unreported | 139 (70) | 256 (80) | 205 (90) |
| % of all events unreported‡ | 50 | 66 | 78 |
| No. patients with ≥ 1 event, n (%) | 110 (47) | 241 (32) | 173 (29) |
| Range of events/person | 1–6 | 1–4 | 1–4 |
| Median time to first event, d | 46 | 30 | 32 |
| Rate, pp/py | 1.90 | 1.92 | 1.72 |
| Parameter | Mpex, 6 mo (N = 235) | AZ 1, 3 mo (N = 749) | AZ 2, 3 mo (N = 597) |
|---|---|---|---|
| Medically treated exacerbations, f | 137 | 132 | 59 |
| Moderate (clinic visit), f | 104 (76%) | 54 (92%) | 119 (90%) |
| EXACT severity, mean (SD) | 53.3* (10.0) | 54.2* (10.4)† | 56.8* (12.3) |
| Change from baseline | 12.7 (9.6) | 10.0 (10.8) | 10.8 (10.4) |
| % Change from baseline | 34% (28) | 28% (35) | 30% (41) |
| Severe (hospitalizations), f | 33 (24%) | 13 (10%) | 5 (8%) |
| EXACT severity, mean (SD) | 53.8 (11.0) | 62.5 (13.3) | 67.4 (14.4) |
| Change from baseline | 13.3 (10.1) | 21.5 (12.7) | 18.3 (14.3) |
| % Change from baseline | 35% (29) | 64% (49) | 40% (36) |
| Symptom (EXACT)-defined events, f | 198 | 320 | 229 |
| All events, mean,‡ (SD) | 57.4 (13.2) | 58.2 (12.9) | 61.2 (12.5) |
| Change from baseline | 20.8 (7.2) | 20.2 (7.7) | 20.1 (6.9) |
| % Change from baseline | 62% (28) | 59% (33) | 55% (32) |
| Unreported, f‡ | 139 | 256 | 205 |
| Mean‡ (SD) | 55.7* (14.2) | 57.0* (13.1) | 60.6* (12.4) |
| Change from baseline | 20.0 (6.7) | 19.4 (7.1) | 19.7 (6.4) |
| % Change from baseline | 62% (29) | 57% (31) | 53% (28) |
| *NS (P = 0.14) | *(P = 0.0281) | *(P = 0.0464) | |
| Reported, f§ | 59 | 64 | 24 |
| Moderate, mean (SD) | 60.8 (10.0) | 62.5 (11.5) | 64.2 (10.0) |
| No. events (f) | 45 | 54 | 22 |
| Change from baseline | 22.4 (8.5) | 22.2 (9.5) | 21.0 (7.7) |
| % Change from baseline | 61% (28) | 60% (40) | 61% (54) |
| Severe, mean (SD) | 64.2 (6.3) | 66.0 (9.9) | 83.0, 100.0ll |
| No. events (f) | 14 | 10 | 2 |
| Change from baseline | 23.4 (6.8) | 29.4 (6.8) | 41.9, 50.1ll |
| % Change from baseline | 60% (24) | 93% (48) | 101%, 102%ll |
| Parameter | Mpex, 6 mo (N = 235) | AZ 1, 3 mo (N = 749) | AZ 2, 3 mo (N = 597) |
|---|---|---|---|
| All events | |||
| MTEs, f | 137 | 132 | 59 |
| Moderate (clinic visit), f | 104 | 119 | 54 |
| Mean d* (SD) | 10.0 (8.1) | 7.5 (5.5) | 6.6 (3.2) |
| Severe (hospitalization), f | 33 | 13 | 5 |
| Mean d* (SD) | 15.7 (8.0) | 10.8 (5.6) | 14.0 (6.1) |
| Symptom (EXACT)-defined Events | |||
| All resolved events,† f | 158 | 192 | 152 |
| Mean d (SD) | 15.9 (18.71) | 12.5 (12.53) | 10.8 (10.42) |
| Unreported,† f | 111 | 154 | 138 |
| Mean d (SD) | 15.3 (17.4) | 12.7 (12.6) | 10.1 (10.0) |
| Difference: moderate MTE vs unreported symptom-defined events | |||
| Median d | 8 vs 9, NS (P = 0.25)‡ | 7 vs 8, (P = 0.006)‡ | 6 vs 7, NS (P = 0.17)‡ |
| MTEs with corresponding symptom-defined events§ | |||
| Moderate (clinic visit), f | 45 | 54 | 22 |
| Treatment-based | |||
| Mean d of treatment‡ | 10.2 (7.8) | 8.9 (6.4) | 7.4 (3.2) |
| Symptom (EXACT)-based | |||
| Mean d (SD) | 29.3 (39.1) | 17.5 (21.5) | 25.0 (21.3) |
| Difference | |||
| Median d | 8 vs 14, (P = 0.0062)‡ | 8.5 vs 9, NS (P = 0.11)‡ | 6.5 vs 16.5, (P = 0.0001)‡ |
| Severe (hospitalization), f | 14 | 10 | 2 |
| Treatment-based | |||
| Mean d of treatment‡ | 15.1 (6.3) | 10.9 (6.2) | 9, 21ll |
| Median, mode | 16, 9 | 8.5, 4 | N/A |
| Symptom (EXACT)-based | |||
| Mean d (SD) | 22.7 (34.9) | 20.9 (23.3) | 3.0, 12.0ll |
| Median, mode | 12, 9 | 14, 2 | N/A |
Figure 1. Survival probability curves for medically treated and symptom (EXAcerbations of Chronic Pulmonary Disease Tool [EXACT])-defined events by dataset. (A) Mpex dataset (6 mo; N = 235). (B) AZ 1 dataset (3 mo; N = 749). (C) AZ 2 dataset (3 mo; N = 597). MTE = medically treated exacerbation.
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Figure 2. Mean EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) scores, Day −21 to Day +28 of first medically treated exacerbation (MTE) and unreported symptom (EXACT)-defined event by dataset. (A) Mpex dataset. (B) AZ 1 dataset. (C) AZ 2 dataset.
[More] [Minimize]Mean within-person EXACT score changes with MTEs were similar across the three trials (Table 5), with moderate MTEs associated with a 28 to 34% symptomatic change from baseline. Percent change for unreported events ranged from 53 to 62%. The threshold for an EXACT event was reached in 44, 53, and 44% of MTEs across the three trials, respectively (moderate: 44, 50, 43%; severe: 42, 85, 60%). For corresponding events, the median time between EXACT-defined onset and Day 1 of the MTE in each of the three trials was 2, 6, and 4 days, respectively (moderate: 2, 5, 3; severe: 1, 14, 4).
In each of the three trials, the severity of symptoms associated with unreported EXACT events were the same or worse (P < 0.05) than MTEs (Table 5). Similarly, EXACT events were as long or longer (P < 0.01) than MTEs, with the latter duration defined by treatment (Table 6). For MTEs with a corresponding EXACT event, symptom duration exceeded treatment duration in two of the three trials (P < 0.01), with a median difference of 6 and 10 days.
This research builds on results of the first validation study for the EXACT (27) by showing the performance of the measure in three independent, prospective, longitudinal randomized controlled trials of symptomatic patients with moderate to severe COPD at risk of exacerbation. Each trial enrolled patients during the stable state and followed them for 3 to 6 months. The patient populations differed in terms of setting (global region), maintenance therapies, and degree of airway obstruction.
Consistent with previous estimates (27), EXACT scores exhibited high levels of internal consistency, strong test–retest reliability, and low SEM values in each sample, indicating a high degree of score precision with minimal error attenuation bias in tests of validity, change, and treatment efficacy. Validity was evident in the relationship between the EXACT and SGRQ, with coefficients from the Mpex data similar to those reported in the first validation study where EXACT scores correlated with SGRQ scores as follows: SGRQ Total: rs = 0.64; Symptoms: rs = 0.56; Activity: rs = 0.46; and Impact: rs = 0.62. In the AZ trials, correlations with the BCSS also supported concurrent validity. The weak relationship with FEV1 was as expected. Correspondences between EXACT-defined events and other indicators of patient worsening were at least as strong as those observed for MTEs, with the exception of contact with a clinic or change in medications—which, of course, define MTEs. Patterns and changes in EXACT scores around MTEs provided further evidence of validity.
The proportion of MTEs reaching the score threshold for an EXACT-defined event (44–53%) suggests the algorithm provides a conservative estimate of unreported events. An imperfect relationship between MTEs and symptom-defined events should be expected for several reasons. First, similar to other trials, clinic visits and hospitalization occurrences and dates were based on patient recall during study visits, which is likely to result in recall error. Second, patients choose to call or see their clinician for a variety of reasons, including clinician instructions, change in other health parameters, and timing (day of the week, holidays, etc.), all of which are not part of the symptomatic definition of exacerbation. Third, clinicians see patients and select treatments for a variety of reasons, including professional preferences, past experiences with a particular patient, comorbid conditions, family concerns, and/or the patient’s reduced capacity for self-care or need for professional observation. Although one might be tempted to reduce the EXACT’s threshold rule to increase the correspondence between symptom-defined and MTEs, this would increase the number of unreported events above rates reported previously. The sustained 9- and 12-point rule is substantially above the 3- to 5-point intrasubject (normal day-to-day variability) for consistency with the clinical definition of COPD exacerbations and confidence that these events are not simply minor symptomatic variances. Data on severity and duration of MTEs and EXACT events and the similarity in symptomatic patterns of change with these events across the three trials support this premise.
In terms of frequency estimates, the proportion of patients with MTEs and the MTE exacerbation rate in the Mpex sample were consistent with those previously reported for 6-month trials of moderate to severe high-risk patients (36–38). The percentage of patients with at least one symptom-defined event (47%) was similar to results reported by Bourbeau and colleagues (36), who found that 42% of the participants in their study experienced a symptom diary–defined exacerbation over a 6-month period. In 1-year studies using daily symptom dairies, O’Reilly and colleagues (39) found that 77% of patients experienced a symptom-defined exacerbation, and Seemungal and colleagues (15) reported this in 87% of patients. Similarly, 88% of the participants in a smaller, naturalistic study of exacerbations and physical activity followed for 135 days (n = 17) experienced symptom (EXACT)-defined events (27, with 9 medically treated) (40).
Consistent with the literature, symptom-defined events were more frequent than MTEs across all three studies, with survival analyses showing these events occurred earlier. The 50% unreported event rate in the 6-month study is similar to rates reported by Langsetmo and colleagues (14) (67% over 6 months) and Seemungal and colleagues (15) (50% over 2.5 yr). The higher proportion of unreported events in the AZ trials may be associated with the lower MTE rate, less severe airway obstruction, fewer comorbidities, or the trial and treatment settings, with any or all of these factors influencing decisions to self-treat rather than seek care. Results across the three trials and previous research suggest that limiting measurement of exacerbations to MTEs underestimates the frequency of these events and overstates clinical impressions or conclusions that patients who have not been seen for an exacerbation are “stable.”
The EXACT was also designed to serve as a standardized measure of symptom severity during exacerbations. Severity of EXACT events were remarkably consistent across the three trials (57–61) and similar to those reported by Halpin and colleagues (41) and Ehsan and colleagues (40). In two of the three datasets, unreported events were statistically more severe than moderate MTEs. Given intrasubject variability of 3 to 5 points, the mean differences (< 4 points) would not be considered clinically meaningful. These results suggest the EXACT threshold rule captures events that are symptomatically equivalent to moderate MTEs and that unreported events are not symptomatically milder; they are simply unseen. In these studies, scores in hospitalized patients should be interpreted with caution due to the small number of events.
Consistent with historical definitions, each trial defined MTE duration by length of pharmacologic treatment or hospitalization. Data provided by the EXACT suggest that symptoms begin before the initiation of therapy, as one might expect, and continue beyond the last day of treatment. Unreported events lasted an average of 10 to 15 days, consistent with the symptom duration reported by Miravitlles and colleagues (42) (mean, 11 days) and Seemungal and colleagues (43) (median, 7 days). Thus, these events are not limited to a short series of “bad days” but are as symptomatic and at least as long as those seen and treated in the clinic. The extent to which treatment might reduce their severity or length is an area for further investigation.
There is evidence that exacerbations, reported and unreported, seriously affect how patients feel and function and adversely impact short- and long-term health outcomes (3, 6, 14–16, 26, 42, 44–49). Results to date suggest the EXACT is providing important information on the symptomatic nature of MTEs and insight into the frequency, severity, and duration of unreported events that will further our understanding of the natural history of exacerbations of COPD and the effects of treatment. Areas for further research include decision making related to care seeking and treatment; the relationship between stable-state symptoms and exacerbation rate, severity, and duration; exacerbation characteristics in subjects with mild airway obstruction, diverse backgrounds, and specific comorbidities; exacerbation characteristics over longer periods of time; and the relationship between frequency of symptom-defined events and quality of life, FEV1 decline, morbidity, and mortality, among others.
In addition to prevention trials and prospective natural history studies, the EXACT was designed for use in acute treatment trials, including those testing the efficacy of antimicrobial therapies (23). Although results of studies to date support the validity and reliability of the EXACT for evaluating exacerbations of COPD, its use and further testing in acute trials is warranted. The suitability of using the EXACT in clinical practice has not been assessed and would require further research, including ease of use with smart phones, prospective scoring methods, and score performance in diverse clinical samples, among others.
Results across three independent datasets suggest the EXACT is a useful instrument for assessing the frequency, severity, and duration of unreported symptom-defined events and standardizing the symptomatic assessment of clinically treated exacerbations, offering a comprehensive method for assessing exacerbations of COPD and the effects of treatment with implications for further research.
The authors thank Mpex (now Aptalis) for providing the 6-month trial dataset (Mpex), and AstraZeneca for providing the two 3-month trial datasets (AZ 1 and AZ 2) used in these analyses. The authors also thank the following Evidera staff: Christie Houle for assistance with the statistical analysis plans and data analyses; Marilyn Stolar and Wen-Hung Chen for their statistical consultation during analyses; Ray Hsieh and Ren Yu for SAS programming; Elizabeth Dansie for her help preparing the online supplement; and Kathryn Miller for her assistance with formatting tables, figures, and this manuscript. They also thank Dr. Jeff Loutit of Mpex and Drs. Mitchell Goldman and Sulabha Ramachandran of AstraZeneca for facilitating data access and for their comments on an earlier version of this paper. This work was supported, in part, by unrestricted funds provided to Evidera’s EXACT-PRO Initiative by the following companies: AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer. These companies did not modify or approve the study design, analyses, or manuscript.
| 1 . | Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD. 2011 [accessed 2013 Aug]. Available from: http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.pdf. |
| 2 . | National Heart Lung and Blood Institute. Morbidity and mortality chartbook on cardiovascular, lung and blood diseases. Bethesda, MD: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 2009 [accessed 2013 Aug]. Available from: http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf |
| 3 . | Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847–852. |
| 4 . | Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest 2002;121:121S–126S. |
| 5 . | Ries AL. Impact of chronic obstructive pulmonary disease on quality of life: the role of dyspnea. Am J Med 2006;119:12–20. |
| 6 . | Spencer S, Calverley PM, Sherwood Burge P, Jones PW; ISOLDE Study Group. Inhaled Steroids in Obstructive Lung Disease. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:122–128. |
| 7 . | 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. |
| 8 . | Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet 2007;370:765–773. |
| 9 . | Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006;3:e442. |
| 10 . | Brusse-Keizer M, van der Palen J, van der Valk P, Hendrix R, Kerstjens H. Clinical predictors of exacerbation frequency in chronic obstructive pulmonary disease. Clin Respir J 2011;5:227–234. |
| 11 . | Tashkin DP. Frequent exacerbations of chronic obstructive pulmonary disease—a distinct phenotype? N Engl J Med 2010;363:1183–1184. |
| 12 . | Calverley P, Pauwels Dagger R, Löfdahl CG, Svensson K, Higenbottam T, Carlsson LG, Ståhl E. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD. Eur Respir J 2005;26:406–413. |
| 13 . | Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000;117:398S–401S. |
| 14 . | Langsetmo L, Platt RW, Ernst P, Bourbeau J. Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med 2008;177:396–401. |
| 15 . | Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418–1422. |
| 16 . | Xu W, Collet JP, Shapiro S, Lin Y, Yang T, Wang C, Bourbeau J. Negative impacts of unreported COPD exacerbations on health-related quality of life at 1 year. Eur Respir J 2010;35:1022–1030. |
| 17 . | Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196–204. |
| 18 . | Aaron SD, Donaldson GC, Whitmore GA, Hurst JR, Ramsay T, Wedzicha JA. Time course and pattern of COPD exacerbation onset. Thorax 2012;67:238–243. |
| 19 . | Quint JK, Donaldson GC, Hurst JR, Goldring JJ, Seemungal TR, Wedzicha JA. Predictive accuracy of patient-reported exacerbation frequency in COPD. Eur Respir J 2011;37:501–507. |
| 20 . | European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), Efficacy Working Party (EWP). Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. EMEA/CHMP/EWP/139391/2004. 2005 Jul [accessed 2013 Aug]. Available from: http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003637.pdf. |
| 21 . | 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. |
| 22 . | Food and Drug Administration. Draft guidance for industry on chronic obstructive pulmonary disease: developing drugs for treatment. Fed Regist 2007;72:63618. |
| 23 . | Food and Drug Administration. Guidance for industry on acute bacterial exacerbations of chronic bronchitis in patients with chronic obstructive pulmonary disease: developing antimicrobial drugs for treatment. Fed Regist 2012;77:2012–24035. |
| 24 . | 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. |
| 25 . | Leidy NK, Murray LT. Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS. COPD 2013;10:393–398. |
| 26 . | 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. |
| 27 . | 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. |
| 28 . | 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. |
| 29 . | 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. |
| 30 . | 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. |
| 31 . | 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. |
| 32 . | 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. |
| 33 . | 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:S59–70. |
| 34 . | 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. |
| 35 . | Meguro M, Barley EA, Spencer S, Jones PW. Development and validation of an improved, COPD-specific version of the St. George Respiratory Questionnaire. Chest 2007;132:456–463. |
| 36 . | Bourbeau J, Ford G, Zackon H, Pinsky N, Lee J, Ruberto G. Impact on patients’ health status following early identification of a COPD exacerbation. Eur Respir J 2007;30:907–913. |
| 37 . | Donohue JF, Fogarty C, Lötvall J, Mahler DA, Worth H, Yorgancioglu A, Iqbal A, Swales J, Owen R, Higgins M, et al.; INHANCE Study Investigators. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010;182:155–162. |
| 38 . | He ZY, Ou LM, Zhang JQ, Bai J, Liu GN, Li MH, Deng JM, MacNee W, Zhong XN. Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease. Respiration 2010;80:445–452. |
| 39 . | O’Reilly JF, Williams AE, Holt K, Rice L. Defining COPD exacerbations: impact on estimation of incidence and burden in primary care. Prim Care Respir J 2006;15:346–353. |
| 40 . | Ehsan M, Khan R, Wakefield D, Qureshi A, Murray L, Zuwallack R, Leidy NK. A longitudinal study evaluating the effect of exacerbations on physical activity in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc 2013;10:559–564. |
| 41 . | Halpin DM, Laing-Morton T, Spedding S, Levy ML, Coyle P, Lewis J, Newbold P, Marno P. A randomised controlled trial of the effect of automated interactive calling combined with a health risk forecast on frequency and severity of exacerbations of COPD assessed clinically and using EXACT PRO. Prim Care Respir J 2011;20:324–331, 2 p following 331. |
| 42 . | Miravitlles M, Anzueto A, Legnani D, Forstmeier L, Fargel M. Patient’s perception of exacerbations of COPD—the PERCEIVE study. Respir Med 2007;101:453–460. |
| 43 . | Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608–1613. |
| 44 . | Adams R, Chavannes N, Jones K, Ostergaard MS, Price D. Exacerbations of chronic obstructive pulmonary disease—a patients’ perspective. Prim Care Respir J 2006;15:102–109. |
| 45 . | Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev 2010;19:113–118. |
| 46 . | Anzueto A, Leimer I, Kesten S. Impact of frequency of COPD exacerbations on pulmonary function, health status and clinical outcomes. Int J Chron Obstruct Pulmon Dis 2009;4:245–251. |
| 47 . | Haughney J, Partridge MR, Vogelmeier C, Larsson T, Kessler R, Ståhl E, Brice R, Löfdahl CG. Exacerbations of COPD: quantifying the patient’s perspective using discrete choice modelling. Eur Respir J 2005;26:623–629. |
| 48 . | Kessler R, Ståhl E, Vogelmeier C, Haughney J, Trudeau E, Löfdahl CG, Partridge MR. Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study. Chest 2006;130:133–142. |
| 49 . | Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL, Masa F, Verea H, Murio C, Ros F, Vidal R; IMPAC Study Group. Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study. Thorax 2004;59:387–395. |
Supported through unrestricted funds from the following companies: AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer, with Mpex providing in-kind contributions through data access.
Author Contributions: Each author contributed substantially to the research described in this paper, including contributions to the concept and design, analyses, and interpretation of the data. N.K.L. and L.T.M. supervised acquisition of the databases, design and execution of the statistical analysis plans, and drafting the manuscript. N.K.L. revised the paper in response to coauthor and referee comments. All authors reviewed and approved this version of the paper before submission.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Author disclosures are available with the text of this article at www.atsjournals.org.
