Clinical trial NCT02088216
Conditions: Non-Cystic Fibrosis Bronchiectasis
Keywords: N-acetylcysteine； Bronchiectasis； Acute exacerbations； Antioxidant； Anti-inflammatory
Sponsor: Qilu Hospital of Shandong University
Start date: 2014-04-01; Completion date: 2018-03-30
Enrollment: 161 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Objective: To evaluate whether long-term oral N-acetylcysteine as an expectorant drug can reduce the frequency of acute exacerbations of patients with non-cystic fibrosis bronchiectasis and improve their quality of life.

Methods: Patients with non-cystic fibrosis bronchiectasis will be randomly assigned to the observer group (participants receive 600 mg of oral N-acetylcysteine BID for 12 months) or the control group (participants receive oral tablet BID for 12 months). The primary endpoint was the frequency of acute exacerbations.

Expected results: Compared with the control group, the frequency of acute exacerbations of the observer Group will decrease significantly.

Hypothesis: Long-term oral N-acetylcysteine can reduce the frequency of acute exacerbations of patients with non-cystic fibrosis bronchiectasis and improve their quality of life.

Detailed description:
Objective: N-acetylcysteine is a classic mucolytic agent. This study aimed to investigate the efficacy and safety of N-acetylcysteine on the risk of exacerbations in bronchiectasis patients.

Methods: A prospective, randomized, controlled trial was conducted between April 1, 2014 and December 31, 2016 in five general hospitals in Shandong Province, China. Adult bronchiectasis patients with at last two exacerbations in the past year were potentially eligible. Patients were randomly assigned to receive oral N-acetylcysteine (600 mg, twice daily, 12 months) or on-demand treatment.

Results: A total of 161 patients were eligible for randomization (81 to the N-acetylcysteine group and 80 to the control group). During the 12-month follow-up, the incidence of exacerbations in the N-acetylcysteine group was significantly lower than that in the control group (1.31 vs. 1.98 exacerbations per patient-year; risk ratio, 0.41; 95% CI, 0.17-0.66; P = 0.0011). The median number of exacerbations in the N-acetylcysteine group was 1 (0.5-2), compared with 2 (1-2) in the control group (U=-2.95, P = 0.003). No severe adverse events were reported in the intervention group.

Conclusion: The long-term use of N-acetylcysteine is able to reduce the risk of exacerbations for bronchiectasis patients.

Arms: arm 1: Participants received 600 mg of oral N-acetylcysteine BID for 12 months. arm 2: Participants received as-needed therapy.
Interventions: intervention 1: N-acetylcysteine intervention 2: On-demand treatment
Intervention descriptions: intervention 1: 600mg po twice a day for 12 months intervention 2: receive as-needed therapy

Protocol documents:
Prot_000.pdf: 
 
Effect of N-acetylcysteine on Exacerbations of Bronchiectasis 
(BENE): a randomized controlled trial 
 
Official Title: Effect of N-acetylcysteine on Exacerbations of Bronchiectasis (BENE): 
a randomized controlled trial 
Trial registration: ClinicalTrials.gov (NCT02088216) (Registered date: March 5, 
2014) 
Document Date: November 2, 2018 


 
MATERIALS AND METHODS 
Study subjects 
Bronchiectasis was diagnosed based on the clinical manifestations and 
high-resolution computed tomography scans. Patients were screened for potential 
eligibility at five general hospitals in Shandong Province of China from April 1, 2014 
to December 31, 2016. The inclusion criteria were as follows: 1) subjects were aged 
18–80 years old; 2) a diagnosis of idiopathic or post-infective bronchiectasis was 
made; and 3) patients had at least two exacerbations in the past year and were in a 
stable state for at least 4 weeks prior to the primary enrollment. Patients were 
excluded if they fulfilled any of the following criteria: current smokers; cigarette 
smoking within 6 months; cystic fibrosis or other etiologies (such as 
immunodeficiency, allergic bronchopulmonary aspergillosis, traction bronchiectasis 
caused by emphysema, advanced pulmonary fibrosis, etc.); pulmonary function test 
results showing a forced expiratory volume in 1 s (FEV1) ≤ 30% of the predicted 
value; a history of severe cardiovascular or neurological disease; comorbidity with 
liver disease, kidney disease, malignant tumor, gastric ulcer, or intestinal 
malabsorption; a known allergy to N-acetylcysteine; pregnancy or lactation (for 
women); a history of prior macrolide use of more than 1 week; and poor compliance. 
This study was registered at ClinicalTrials.gov (NCT02088216) and was approved by 
the ethics committees of the five participating hospitals. Informed consents were 
obtained from all patients. 
Study design 
The Effect of N-acetylcysteine on Exacerbations of Bronchiectasis (BENE) 
study was a prospective, randomized, controlled, multicenter clinical trial. The main 
study objective was to assess whether the long-term use of oral N-acetylcysteine (600 
mg, twice daily, 12 months) might reduce the incidence of exacerbations and improve 
the quality of life in patients with bronchiectasis. According to previous clinical data 
on exacerbations of bronchiectasis and the inclusion criteria that a subpopulation of 
bronchiectasis patients with at least two exacerbations in the past year were included 
in our study, we hypothesized that the baseline frequency of exacerbations was 3. Due 


 
to the lack of clinical data on the efficiency of N-acetylcysteine in the treatment of 
bronchiectasis, we assumed that approximately 154 patients would need to be enrolled 
in this study to have 80% power to detect a reduction of at least 33% in the yearly 
exacerbation incidence, assuming a two-sided α level of 0.05 and 20% attrition. 
Methods 
The sequence was generated by a computer, and the patients who met the 
criteria were allocated in a 1:1 ratio to receive either oral N-acetylcysteine (600 mg, 
twice daily) or control (receive as-needed therapy) for 12 months. All the participants 
were followed for up to 12 months. Outpatient and/or telephone visits were obtained 
for the primary and secondary outcomes at 1, 3, 6, 9, and 12 months. Moreover, 
compliance and adverse reactions were also documented. The treatment strategy 
based on current guidelines was instituted for patients with exacerbations. Meanwhile, 
patients in the N-acetylcysteine group were also required to receive oral 
N-acetylcysteine (600 mg, twice daily) during the study period. For the control group, 
interventions would be discontinued once the patient recovered from the exacerbation. 
Maintenance therapies that had already started in patients with pulmonary ventilation 
dysfunction prior to enrollment, such as short-acting bronchodilators, long-acting 
bronchodilators, inhaled glucocorticoids, or theophylline, were continued during the 
study. However, the use of other mucolytics or expectorants, antioxidant agents, or 
vitamins with antioxidant properties was not recommended. 
Study end-points 
The primary end-point was the incidence of exacerbations in a year, defined as 
the number of all exacerbations associated with bronchiectasis within one year. An 
exacerbation of bronchiectasis is defined by the British Thoracic Society guidelines 
for bronchiectasis. Details regarding symptoms of an exacerbation such as dyspnea, 
sputum volume (collected over 24 h), sputum properties, fever, and persistent upper 
respiratory tract infection were also documented by site investigators from all centers. 
Secondary end-points included the time to the first exacerbation, 24-h sputum 
volume, lung function, inflammation indices, quality of life (assessed by COPD 
assessment test score, CAT score), and adverse events. The volume of 24-h sputum 


 
was measured by a graduated cylinder marked in milliliters. Eligible sputum samples 
were used for testing sputum microbiological culture and antibiotic resistance. 
Pulmonary function was assessed three times before recruitment, and the maximum 
value was used for analysis. Following treatment, pulmonary function was reassessed 
for forced vital capacity (FVC), FEV1, percentage of predicted FEV1, FEV1/FVC 
ratio (FEV1/FVC), and inspiratory capacity, etc. Inflammatory markers including 
serum C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were 
tested at each visit. The severity of bronchiectasis was quantified by high-resolution 
computed tomography (HRCT), and the number of lobes involved was counted 
according to the modified Reiff grade. Furthermore, the degree of dyspnea was 
assessed by the modified Medical Research Council (mMRC) scale. 

SAP_001.pdf: 
 
Effect of N-acetylcysteine on Exacerbations of Bronchiectasis 
(BENE): a randomized controlled trial 
 
Official Title: Effect of N-acetylcysteine on Exacerbations of Bronchiectasis (BENE): 
a randomized controlled trial 
Trial registration: ClinicalTrials.gov (NCT02088216) (Registered date: March 5, 
2014) 
Document Date: November 2, 2018 
 


 
Statistical analyses 
Patients who received at least one assessment visit after randomization were left 
in the original group for analysis of the results. Continuous data were expressed as the 
mean ± standard deviation and were compared using the Student’s t test. Categorical 
variables were expressed as a number (%) and were compared using the χ2 test. 
Number of exacerbations was described by the median (interquartile range, IQR). The 
Mann-Whitney U test was performed to compare the difference in the number of 
exacerbations between the two groups. The primary study end point was the incidence 
of exacerbations, which is a count and follows Poisson distribution. Negative 
binomial regression not including other covariates was employed to compute the risk 
ratio and 95% confidence intervals (CIs) for N-acetylcysteine vs. the control. The 
time to the first exacerbation was described by Kaplan–Meier curves, and the log-rank 
test was used to explore the differences in time to the first exacerbation between the 
two groups. All analyses were conducted with the Statistical Package for the Social 
Sciences (SPSS) software (version 20.0). A p value < 0.05 was considered statistically 
significant.