Early Changes in eDiary COPD Symptoms Predict Clinically Relevant Treatment Response at 12 Weeks: Analysis from the CRYSTAL Study

Figures & data

Table 1. Evaluated questions (EQ3 to EQ9) of an electronic diary symptom questionnaire.

Evening Questions	Possible Answers
EQ1: Number of puffs of rescue medication during the past 24 hours:	0–20 puffs	Not evaluated in this analysis
EQ2: Did you take the study medication as prescribed by your study doctor today?	Yes/No
EQ3: How would you rate your respiratory symptoms last night?	0 = No waking due to symptoms
	1 = Woke up once due to symptoms
	2 = Woke up more than once due to symptoms
	3 = Woke up frequently or could not sleep due to symptoms
EQ4: Did your respiratory symptoms stop you performing your usual daily activities today?	0 = Not at all
	1 = A little
	2 = Quite a lot
	3 = Completely
EQ5: How was your cough during the past 24 hours?	0 = None	Evaluated in this analysis Major symptoms
	1 = Mild
	2 = Moderate
	3 = Severe
EQ6: How was your wheeze during the past 24 hours?	0 = None
	1 = Mild
	2 = Moderate
	3 = Severe
EQ7: How much sputum did you produce the past 24 hours?	0 = None
	1 = Less than 5 mL (1 teaspoon)
	2 = Between 5 and 25 mL (1–5 teaspoons)
	3 = More than 25 mL (5 teaspoons)
EQ8: What color was the sputum you produced during the past 24 hours?	0 = None
	1 = White-grey
	2 = Yellow
	3 = Green
EQ9: During what activities did you first feel breathless in the last 24 hours?	0 = Never or only when running
	1 = When walking uphill or upstairs
	2 = When walking on flat ground
	3 = At rest
EQ10: Did you have a sore throat during the past 24 hours?	0 = No
	1 = Yes, mild
	2 = Yes, moderate	Not evaluated in this analysis Minor symptoms
	3 = Yes, severe
EQ11: Did you have a cold (nasal discharge and/or nasal congestion) during the past 24 hours?	0 = No
	1 = Yes, mild
	2 = Yes, moderate
	3 = Yes, severe
EQ12: Did you have a fever during the past 24 hours?	0 = No
	1 = Yes, mild
	2 = Yes, moderate
	3 = Yes, severe

eDiary, electronic diary.

Table 2. Patients' demographics and baseline characteristics.

Characteristics	Value (N = 4324)
Age, years	64.6 ± 8.30
Men, n (%)	2908 (67.3)
Body mass index, kg/m^2	27.6 ± 5.0
Current smokers, n (%)	2292 (53.0)
Time since COPD diagnosis, years	6.1 ± 5.5
Post-bronchodilator FEV1, L	1.85 ± 0.49
Post-bronchodilator FEV1, % predicted	64.7 ± 8.70
Post-bronchodilator FEV1/FVC	0.57 ± 0.08
Dyspnea—mMRC grade, n (%)
1	2591 (59.9)
≥2	1693 (39.1)
Number of exacerbations in the previous 12 months, n (%)
1	867 (20.1)
≥2	16 (0.4)
Baseline Treatment, n (%)
SABA, SAMA, SABA+SAMA	496 (11.5)
LABA + ICS (fixed dose or free combination)	1059 (24.5)
LABA (only monotherapy)	1193 (27.6)
LAMA (only monotherapy)	1512 (35.0)
Others/NA/Unknown^*	184 (4.3)

Data presented as mean ± SD unless stated otherwise.

^* LAMA + ICS, LABA + LAMA, ICS monotherapy, LABA + LAMA + ICS (triple), systemic corticosteroids, methylxanthines, roflumilast and others.

FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; IND/GLY, indacaterol/glycopyrronium; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council; NA, not available; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist.

Table 3. Mean changes in symptoms on Days 7 and 14 in patients with and without a MCID in trough FEV₁ (≥100 mL; responders and non-responders) at Week 12.

	Responders^*(n = 1680)	Nonresponders (n = 2421)	P-value
Night-time respiratory symptoms
Day7−Day0	−0.042 ± 0.61	−0.022 ± 0.61	0.1664
Day14−Day0	−0.084 ± 0.63	−0.026 ± 0.62	0.0013
Activity impairment
Day7−Day0	−0.056 ± 0.62	−0.016 ± 0.57	0.0613
Day14−Day0	−0.045 ± 0.59	−0.010 ± 0.59	0.1161
Cough
Day7−Day0	−0.041 ± 0.67	−0.041 ± 0.66	0.9606
Day14−Day0	−0.096 ± 0.67	−0.083 ± 0.65	0.5513
Wheeze
Day7−Day0	−0.135 ± 0.62	−0.066 ± 0.59	0.0005
Day14−Day0	−0.129 ± 0.62	−0.070 ± 0.62	0.0039
Sputum
Day7−Day0	−0.055 ± 0.59	−0.022 ± 0.56	0.0345
Day14−Day0	−0.086 ± 0.59	−0.045 ± 0.60	0.0146
Sputum color
Day7−Day0	−0.011 ± 0.49	−0.016 ± 0.50	0.7901
Day14−Day0	−0.034 ± 0.50	−0.027 ± 0.53	0.4990
Breathlessness
Day7−Day0	−0.064 ± 0.64	−0.043 ± 0.59	0.3600
Day14−Day0	−0.077 ± 0.63	−0.041 ± 0.62	0.1066

Data presented as mean ± SD.

P-values indicate statistically significant difference.

^* Responders: patients achieved MCID in trough FEV₁ (≥100 mL increase) at Week 12.

FEV₁, forced expiratory volume in 1 second; MCID, minimal clinically important difference.

Figure 1. FEV₁ responders at Week 12 as predicted by the improvement in individual symptoms on Days 7 and 14. The odds ratio and 95% confidence interval (CI) presented are adjusted for age, sex, baseline, baseline dyspnoea index and current smoking status. FEV₁, forced expiratory volume in 1 second.

Table 4. Mean changes in symptoms on Days 7 and 14 in patients with and without a MCID in TDI total score (≥1 unit; responders and non-responders) at Week 12.

	Responders^*(n = 2008)	Nonresponders (n = 1994)	P-value
Night-time respiratory symptoms
Day7−Day0	−0.070 ± 0.62	0.008 ± 0.59	<0.0001
Day14−Day0	−0.098 ± 0.63	−0.001 ± 0.60	<0.0001
Activity impairment
Day7−Day0	−0.065 ± 0.60	0.002 ± 0.59	0.0005
Day14−Day0	−0.062 ± 0.61	0.018 ± 0.58	<0.0001
Cough
Day7−Day0	−0.060 ± 0.66	−0.026 ± 0.66	0.1093
Day14−Day0	−0.110 ± 0.66	−0.062 ± 0.66	0.0229
Wheeze
Day7−Day0	−0.143 ± 0.60	−0.044 ± 0.59	<0.0001
Day14−Day0	−0.147 ± 0.64	−0.040 ± 0.59	<0.0001
Sputum
Day7−Day0	−0.045 ± 0.58	−0.021 ± 0.55	0.2269
Day14−Day0	−0.089 ± 0.60	−0.027 ± 0.58	0.0011
Sputum color
Day7−Day0	−0.028 ± 0.51	−0.002 ± 0.48	0.1373
Day14−Day0	−0.057 ± 0.51	0.000 ± 0.52	0.0011
Breathlessness
Day7−Day0	−0.071 ± 0.61	−0.035 ± 0.62	0.0354
-Day14−Day0	−0.074 ± 0.64	−0.033 ± 0.62	0.0239

Data presented as mean ± SD.

P-values indicate statistically significant difference.

^* Responders: patients achieved MCID in TDI total score (≥1 unit increase) at Week 12.

MCID, minimal clinically important difference; TDI, transition dyspnea index.

Figure 2. TDI responders at Week 12 as predicted by the improvement in individual symptoms on Days 7 and 14. The odds ratio and 95% confidence interval (CI) presented are adjusted for age, sex, baseline trough forced expiratory volume in 1 second (FEV₁) and current smoking status. TDI, transition dyspnea index.