The Effect of Maintenance Treatment with Erdosteine on Exacerbation Treatment and Health Status in Patients with COPD: A Post-Hoc Analysis of the RESTORE Dataset

Figures & data

Figure 1 Flow chart of patients in the analysis by treatment group, severity of COPD, exacerbation status, and severity of exacerbations (ITT population). All numbers refer to numbers of patients.

Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; ITT, intention-to-treat.

Table 1 Demographic and Baseline Characteristics of Patients (ITT Population)

	GOLD 2 Patients^a (N = 254)		GOLD 3 Patients^b (N = 191)		All RESTORE Patients (N = 445)
	Erdosteine	Placebo	Erdosteine	Placebo	Erdosteine	Placebo
Patients, n	126	128	89	102	215	230
Age, years	64.8 (7.6)	66.1 (7.3)	62.9 (8.9)	63.1 (8.8)	63.8 (8.3)	64.1 (8.2)
Male, %	65.9	72.7	74.5	73.9	71.8	74.6
BMI, kg/m^2	27.6 (5.0)	28.2 (5.6)	27.0 (4.8)	27.8 (5.1)	27.2 (5.3)	28.0 (5.4)
Smoking status, %
Current smoker	31.7	28.9	25.8	27.5	27.1	28.0
Ex-smoker	68.3	71.1	74.2	72.5	72.9	72.0
ICS, n (%)	88 (69.8)	91 (71.1)	80 (89.9)*	94 (92.2)*	165 (75.8)	173 (75.2)
FEV1, L	1.61 (0.35)	1.68 (0.42)	1.26 (0.39)*	1.23 (0.43)*	1.43 (0.40)	1.46 (0.47)
FEV1, % predicted	59.88 (6.3)	61.08 (6.8)	47.21 (10.83)*	46.72 (11.69)*	51.45 (12.82)	54.38 (13.33)
FVC, L	2.82 (0.66)	2.89 (0.72)	2.59 (0.99)*	2.54 (0.97)*	2.74 (0.93)	2.74 (0.94)
Post-BD FEV1/FVC, ratio %	58.76 (8.8)	58.00 (8.1)	51.92 (9.88)*	50.81 (10.03)*	54.01 (11.3)	53.26 (10.8)

Notes: Data are presented as mean (standard deviation) unless indicated otherwise. ^aGOLD 2: moderate COPD group, determined post-hoc and based on GOLD 2022 spirometry criteria (FEV₁ 50‒79% predicted); ^bGOLD 3: severe COPD group, determined post-hoc and based on GOLD 2022 spirometry criteria (FEV₁ 30‒49% predicted). *P < 0.05 vs GOLD 2 group. Categorical variables compared as continuous depending on distribution: Student’s t-test for unpaired samples (if normal distribution) or Mann–Whitney U-test. All comparisons between erdosteine and placebo groups were non-significant.

Abbreviations: BD, bronchodilator; BMI, body mass index; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, global initiative for chronic obstructive lung disease; ICS, inhaled corticosteroid; ITT, intention-to-treat.

Figure 2 Mean SGRQ total score for GOLD 2 patients with moderate COPD who experienced exacerbations in each treatment group (erdosteine or placebo) and for the subgroups by exacerbation severity (mild or moderate-to-severe). A lower score represents a better HRQoL. Patients may have experienced more than one exacerbation, but those in the mild exacerbations subgroup only experienced mild exacerbations, while those in the moderate-to-severe exacerbations subgroup may also have experienced mild exacerbations. The n value for each treatment group is the number of patients with exacerbations. There were 127 exacerbations overall (89 mild exacerbations and 38 moderate-to-severe exacerbations). Analysis was conducted in the ITT population and based on ANCOVA model including fixed effects of treatment. P values given above the columns are for significant changes in trend over time for each treatment and for the treatment comparison; they were analyzed using the Residual Maximum Likelihood or least squares method. *P < 0.05 versus placebo at each timepoint.

Abbreviations: ANCOVA, analysis of covariance; COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; HRQoL, health-related quality of life; ITT, intention-to-treat; SGRQ, St George’s respiratory questionnaire.

Table 2 Patient Subjective Assessment of Disease Severity Over Time by COPD Severity, Exacerbation Severity and Treatment Group

Exacerbation Severity^a (Number of Exacerbations)	Treatment	Mean (95% CI) Disease Severity Score (Patient Assessed)			P-value for Trend	P-value for Treatment Comparison
		Baseline	6 Months	12 Months
GOLD 2 patients (N = 254)
All exacerbations (n = 127)	Erdosteine	1.49 (1.14‒1.99)	1.37 (1.09‒1.99)*	1.25 (0.79‒1.95)*	0.021	< 0.001
	Placebo	1.50 (1.15‒2.08)	1.51 (1.15‒2.08)	1.54 (1.19‒2.11)	0.129
Mild exacerbations (n = 89)	Erdosteine	1.26 (1.12‒1.34)	1.09 (1.04‒1.29)*	0.92 (0.72‒1.23)*	0.008	< 0.001
	Placebo	1.29 (1.13‒1.37)	1.31 (1.12‒1.41)	1.35 (1.15‒1.42)	0.218
Moderate-to-severe exacerbations (n = 38)	Erdosteine	1.87 (1.60‒2.04)	1.82 (1.74‒2.03)	1.71 (1.62‒1.99)*	0.044	0.047
	Placebo	1.91 (1.82‒2.14)	1.89 (1.80‒2.15)	1.95 (1.80‒2.18)	0.483
GOLD 3 patients (N = 191)
All exacerbations (n = 330)	Erdosteine	2.10 (1.81‒2.44)	2.03 (1.90‒2.36)	2.08 (1.94‒2.71)	0.534	0.521
	Placebo	2.04 (1.86‒2.47)	2.06 (1.81‒2.44)	2.08 (1.94‒2.71)	0.102
Mild exacerbations (n = 197)	Erdosteine	1.89 (1.70‒2.15)	1.90 (1.78‒2.22)	1.91 (1.82‒2.25)	0.547	0.544
	Placebo	1.86 (1.74‒2.18)	1.92 (1.80‒2.23)	1.93 (1.82‒2.24)	0.094
Moderate-to-severe exacerbations (n = 133)	Erdosteine	2.32 (2.28‒2.47)	2.26 (2.14‒2.39)	2.29 (2.19‒2.82)	0.594	0.601
	Placebo	2.28 (2.14‒2.51)	2.34 (2.23‒2.68)	2.38 (2.22‒2.77)	0.184
All RESTORE patients (N = 445)
All exacerbations (n = 457)	Erdosteine	1.69 (1.61‒1.96)	1.63 (1.41‒1.90)	1.48 (1.41‒1.99)*	0.049	0.027
	Placebo	1.72 (1.45‒1.96)	1.69 (1.43‒1.96)	1.65 (1.50‒1.84)	0.076
Mild exacerbations (n = 286)	Erdosteine	1.52 (1.46‒1.70)	1.46 (1.37‒1.67)	1.41 (1.37‒1.84)*	0.042	0.029
	Placebo	1.49 (1.42‒1.69)	1.50 (1.41‒1.88)	1.48 (1.39‒1.83)	0.423
Moderate-to-severe exacerbations (n = 171)	Erdosteine	1.94 (1.66‒2.24)	1.92 (1.59‒2.21)	1.91 (1.66‒2.29)	0.541	0.453
	Placebo	1.95 (1.69‒2.28)	1.95 (1.62‒2.24)	1.91 (1.66‒2.29)	0.528

Notes: Data are presented as mean (95% CI). Scores range from 0‒4, with higher scores representing worse subjective disease severity. ^aPatients may have experienced more than one exacerbation during the 12 months of treatment; they were grouped as having mild or moderate-to-severe exacerbations. Patients in the moderate-to-severe exacerbations subgroup may also have had mild exacerbations, but patients in the mild exacerbations subgroup did not have moderate-to-severe exacerbations during the 12 months of treatment. The analysis was conducted in the ITT population and was based on an ANCOVA model including the fixed effects of treatment. Changes in trend over time were analyzed using the REML or least squares method. P-values in bold are considered significant (< 0.05). *P < 0.05 vs placebo at each time point.

Abbreviations: ANCOVA, analysis of covariance; CI, confidence interval; GOLD, global initiative for chronic obstructive lung disease; ITT, intention-to-treat; REML, residual maximum likelihood.

Figure 3 Proportion of patients with moderate-to-severe exacerbations who used antibiotics alone and with oral corticosteroids by disease severity (GOLD 2 or 3) and treatment group. The percentage value in italics above each stacked bar is the total percentage of patients treated with antibiotics (with or without oral corticosteroids); the remaining patients with moderate-to-severe exacerbations received oral corticosteroids alone. The P values above the columns are for the comparisons of erdosteine versus placebo for the total percentage of patients treated with antibiotics. The asterisks between columns represent *P < 0.05 for erdosteine versus placebo groups within each antibiotic treatment group (antibiotic + oral corticosteroid or antibiotic alone). Analysis used a Chi-square test followed by Fisher’s exact test.

Abbreviation: GOLD, global initiative for chronic obstructive lung disease.

Table 3 Oral Corticosteroid Total Dose and Average Daily Dose (Prednisolone-Equivalents) Over 12 Months in Patients Experiencing Moderate-to-Severe Exacerbations by COPD Severity and Treatment Group

Corticosteroid Dose	Severity of COPD	Prednisolone-Equivalent Dose (mg)				P-value^a
		Erdosteine		Placebo
		n	Mean (SD)	n	Mean (SD)
Total dose over 12 months	GOLD 2	6	251.9 (31.3)	13	320.5 (33.9)	< 0.001
	GOLD 3	49	491.5 (39.1)	57	507.6 (40.2)	0.761
Average daily dose over 12 months^b	GOLD 2	6	22.1 (3.5)	13	24.1 (3.2)	0.352
	GOLD 3	49	33.9 (3.7)	57	34.3 (3.6)	0.541

Notes: Data are presented as mean (SD). n = number of exacerbating patients treated with systemic corticosteroids. ^aStudent’s t-test for unpaired samples. P-values in bold are considered significant (< 0.05). ^bCalculated as the total dose divided by the mean duration of treatment (in days).

Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; SD, standard deviation.