High-dose oral N-acetylcysteine fails to improve respiratory health status in patients with chronic obstructive pulmonary disease and chronic bronchitis: a randomized, placebo-controlled trial

Figures & data

Table 1 Baseline characteristics

	Placebo (N=22)	N-acetylcysteine (N=23)	P-value
Age, years (mean ± SD)	68.9±8.2	70.1±7.7	0.62
Sex, M/F	19/3	18/5	0.38a
Caucasian race, n (%)	22 (100)	23 (100)	1.00
Smoking history
Current smoker, n (%)	11 (50)	3 (13)	0.006
Pack-years (mean ± SD)	60±40	74±38	0.11a
Respiratory medications at baseline
LAMA, n (%)	15 (68)	18 (78)	0.44
LABA, n (%)	17 (77)	21 (91)	0.19
ICS, n (%)	16 (73)	19 (83)	0.42
Home oxygen, n (%)	6 (27)	14 (61)	0.02
FEV1 (L), mean ± SD	1.15±0.50	1.11±0.44	0.78
% predicted FEV1, mean ± SD	41±12	40±13	0.70
FVC (L), mean ± SD	2.73±0.88	2.65±0.70	0.73
FEV1/FVC, mean ± SD	0.42±0.11	0.43±0.14	0.73
≥1 exacerbation past year, n (%)	16 (73)	18 (78)	0.67
≥1 COPD hospital admission past year, n (%)	7 (32)	5 (22)	0.44
History of cardiovascular disease, n (%)	14 (64)	18 (78)	0.28
SGRQ
Symptoms, mean ± SD	69±18	54±17	0.004a
Activity, mean ± SD	70±22	71±21	0.95a
Impacts, mean ± SD	42±22	37±20	0.39
Total, mean ± SD	56±20	49±17	0.18a
CBSAS, mean ± SD	22.5±8.3	17.6±7.5	0.04
SF-36
Physical, mean ± SD	36±7	38±7	0.05a
Mental, mean ± SD	50±11	50±11	0.93a

Notes:

a Fisher’s exact test was used for categorical measure or Wilcoxon signed-rank sum test was used for continuous measure; if skewness measure for distribution in either group was >0.70, Wilcoxon test was used, and if 50% of expected cell counts were <5, then Fisher’s exact test was used.

Abbreviations: CBSAS, Chronic Bronchitis Symptoms Assessment Scale; F, female; FEV₁, forced expiratory volume in one 1 second; FVC, forced vital capacity; ICS, inhaled corticosteroid; LABA, long-acting beta adrenergic; LAMA, long-acting antimuscarinic; M, male; SGRQ, St George’s Respiratory Questionnaire; SF-36, Short Form-36 Health Survey; SD, standard deviation.

Figure 1 Flow chart of screening, randomization, and follow-up.

Table 2 Changes in survey scores over 8 weeks, according to treatment assignment

	Baseline (mean ± SD)	Study end(mean ± SD)	Change (mean ± SD)	N-acetylcysteine–placebo
				Mean difference (95% CI)	P-value	Adjusted mean difference (95% CI)	P-value
SGRQ
Symptoms
Placebo (n=22)	69.3±17.7	59.5±21.2	−9.8±17.8	6.3 (−4.6, 17.3)	0.25	1.6 (−10.4, 13.5)	0.79
N-acetylcysteine (n=23)	54.2±17.4	50.7±20.3	−3.5±18.6
Activity
Placebo (n=22)	69.8±21.9	66.1±21.5	−3.7±14.5	−0.3 (−8.7, 8.2)	0.95	−1.1 (−8.5, 6.3)	0.76
N-acetylcysteine (n=23)	70.4±20.9	66.4±16.9	−4.0±13.6
Impact
Placebo (n=22)	42.3±22.5	34.8±22.8	−7.5±20.1	3.0 (−7.6, 13.6)	0.57	−0.4 (−10.0, 9.2)	0.93
N-acetylcysteine (n=23)	36.9±19.9	32.4±17.9	−4.5±14.9
Total
Placebo (n=22)	55.5±20.0	48.4±20.7	−7.1±16.1	3.2 (−5.3, 11.8)	0.45	0.1 (−7.8, 8.1)	0.97
N-acetylcysteine (n=23)	49.6±16.9	45.8±14.9	−3.9±12.1
CBSAS
Placebo (n=22)	22.5±8.3	19.6±8.0	−2.8±5.2	0.6 (−2.4, 3.6)	0.69	−0.8 (−3.8, 2.2)	0.60
N-acetylcysteine (n=23)	17.6±7.5	15.4±7.2	−2.2±4.8
SF-36
Physical
Placebo (n=22)	35.6±7.5	36.2±9.2	0.6±7.6	−1.9 (−6.0, 2.1)	0.34	−0.6 (−4.4, 3.2)	0.75
N-acetylcysteine (n=23)	38.4±6.5	37.1±6.3	−1.3±5.8
Mental
Placebo (n=22)	49.5±10.8	47.9±13.5	−1.6±12.3	2.7 (−3.5, 8.8)	0.38	3.2 (−2.8, 9.1)	0.29
N-acetylcysteine (n=23)	50.2±10.9	51.2±12.6	1.0±7.6

Notes: Results presented as mean ± SD. Adjusted mean differences in change scores estimated in the regression model for change score using intervention, baseline outcome measure, age, sex, and percentage predicted FEV₁ as explanatory variables.

Abbreviations: CBSAS, Chronic Bronchitis Symptoms Assessment Scale; FEV₁, forced expiratory volume in 1 second; SF-36, Short Form-36 Health Survey; SGRQ, St George’s Respiratory Questionnaire; SD, standard deviation; CI, confidence interval.

Table 3 Changes in lung function over 8 weeks, according to treatment assignment

	Baseline (mean ± SD)	Study end (mean ± SD)	Change (mean ± SD)	N-acetylcysteine–placebo
				Mean difference (95% CI)	P-value	Adjusted mean difference (95% CI)	P-value
FEV1 (L)
Placebo (n=21)	1.18±0.49	1.12±0.47	−0.06±0.11	0.06 (0.00, 0.13)	0.04	0.06 (−0.01, 0.12)	0.10
N-acetylcysteine (n=23)	1.14±0.42	1.14±0.42	0.00±0.10
% predicted FEV1 (%)
Placebo (n=21)	41.1±12.1	38.9±12.4	−2.3±5.6	2.1 (−0.9, 5.0)	0.16	1.8 (−1.1, 4.8)	0.22
N-acetylcysteine (n=23)	39.1±13.2	38.9±13.1	−0.2±4.0
FVC (L)
Placebo (n=21)	2.82±0.85	2.77±0.84	−0.05±0.27	0.09 (−0.09, 0.27)	0.31	0.08 (−0.08, 0.26)	0.30
N-acetylcysteine (n=23)	2.71±0.61	2.76±0.57	0.04±0.30
FEV1/FVC
Placebo (n=21)	0.42±0.11	0.40±0.10	−0.02±0.05	0.02 (−0.01, 0.05)	0.14	0.02 (−0.003, 0.045)	0.10
N-acetylcysteine (n=23)	0.42±0.11	0.41±0.10	0.00±0.04

Notes: Results presented as mean ± SD. Adjusted mean differences in change scores estimated in the regression model for change score using intervention, baseline outcome measure, age, sex, and percentage predicted FEV₁ as explanatory variables.

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; SD, standard deviation; CI, confidence interval.

Table 4 Changes in oxidation and inflammation biomarkers over 8 weeks, according to treatment assignment

	Baseline (mean ± SD)	Study end (mean ± SD)	Change (mean ± SD)	N-acetylcysteine–placebo
				Mean difference (95% CI)	P-value	Adjusted mean difference (95% CI)	P-value
GSH (µM)
Placebo (n=15)	0.88±0.55	1.11±0.71	0.23±1.00	−0.10 (−0.99, 0.78)	0.82	0.02 (−0.87, 0.91)	0.97
N-acetylcysteine (n=14)	1.13±0.57	1.26±1.35	0.13±1.32
GSSG (µM)
Placebo (n=15)	0.08±0.06	0.09±0.07	0.01±0.08	0.02 (−0.07, 0.11)	0.66	0.03 (−0.07, 0.12)	0.55
N-acetylcysteine (n=14)	0.10±0.10	0.13±0.16	0.03±0.16
GSSG/GSH + GSSG (%)
Placebo (n=15)	8.43±5.64	7.52±3.41	−0.91±5.04	3.21 (−1.02, 7.44)	0.13	2.24 (−0.54, 5.40)	0.10
N-acetylcysteine (n=14)	7.31±5.58	9.61±4.36	2.30±6.05
GSH/GSSG redox state (mV)
Placebo (n=15)	−117±16	−120±18	−3±19	11 (−4, 27)	0.15	8 (−6, 22)	0.24
N-acetylcysteine (n=14)	−121±12	−113±15	8±22
Cys (µM)
Placebo (n=15)	1.28±1.50	1.23±2.36	−0.05±1.92	−0.05 (−1.22, 1.12)	0.93	−0.25 (−1.52, 1.02)	0.69
N-acetylcysteine (n=14)	0.87±1.03	0.77±1.09	−0.10±0.97
CySS (µM)
Placebo (n=15)	13.12±8.44	15.67±8.95	2.55±11.96	2.55 (−13.21, 8.11)	0.63	−1.44 (−9.74, 6.85)	0.72
N-acetylcysteine (n=14)	15.52±10.24	15.52±11.59	0.00±15.88
CySS/Cys + CySS (%)
Placebo (n=15)	88.8±13.4	94.0±7.9	5.2±8.0	−2.5 (−8.4, 3.4)	0.39	−0.1 (−4.1, 3.9)	0.96
N-acetylcysteine (n=14)	92.8±9.8	95.5±7.1	2.7±7.4
Cys/CySS redox state (mV)
Placebo (n=15)	−18.6±39.4	−3.7±42.5	14.9±30.3	0.3 (−21.8, 22.4)	0.98	1.6 (−20.4, 23.7)	0.88
N-acetylcysteine (n=14)	−15.7±35.3	−0.5±39.9	15.2±27.5
8-Isoprostane (pg/mL)
Placebo (n=13)	488±413	656±807	168±919	246 (−383, 874)	0.43	144 (−406, 695)	0.59
N-acetylcysteine (n=14)	369±305	782±543	413±654
C-reactive protein (mg/dL)
Placebo (n=20)	4.8±6.3	5.9±10.7	1.1±7.2	−0.3 (−4.7, 4.1)	0.89	−0.3 (−4.9, 4.4)	0.91
N-acetylcysteine (n=21)	5.8±5.2	6.5±7.5	0.8±7.1

Notes: Results presented as mean ± SD. C-reactive protein in serum; all other measures in plasma. Adjusted mean differences in change scores estimated in the regression model for change score using intervention, baseline outcome measure, age, sex, and percentage predicted FEV₁ as explanatory variables.

Abbreviations: Cys, cysteine; CySS, cystine; FEV₁, forced expiratory volume in 1 second; GSH, glutathione; GSSG, glutathione disulfide; SD, standard deviation; CI, confidence interval.

Figure 2 Reported AEs and SAEs, according to treatment assignment.

Note: Each box represents an individual patient.
Abbreviations: AE, adverse event; SAE, serious adverse event.