A double‐blind randomized controlled trial of N‐acetylcysteine (NAC) for the treatment of acute exacerbation of chronic obstructive pulmonary disease (2024)

This is the protocol for the clinical trial ‘A double–blind randomized controlled trial of N‐acetylcysteine (NAC) for the treatment of acute exacerbation of chronic obstructive pulmonary disease’. This study will assess the role of NAC in the treatment of acute COPD exacerbation in terms of clinical, physiological, and laboratory parameters.

Background and rationale

Chronic obstructive pulmonary disease (COPD) is a major chronic lung disease resulting in airflow limitation. Patients with COPD experience gradually deteriorating lung function, which may be complicated by acute exacerbations.1

COPD is currently ranked as the fourth leading cause of death worldwide according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.2 The Global Burden of Disease Study estimated that 3.2 million people died from COPD in 2015, an increase of 11.6% compared with 1990. During the same period, the prevalence of COPD also increased by 44.2% to 174.5 million in 2015.3

The prevalence rates of COPD in Hong Kong for older adults aged ≥60 years were reported to be 25.9% and 12.4% based on two different spirometric definitions (post‐bronchodilator FEV₁/FVC <70% or lower limit of normal range). The crude mortality rate of COPD in Hong Kong was 29.1/100,000, whereas the crude hospitalization rate was 193/100,000 in 2005.4 This disease accounted for over 30,000 inpatient discharge cases and deaths in 2016 and 1223 registered deaths in 2017.

An exacerbation of COPD is defined as an acute worsening of respiratory symptoms resulting in the need for additional therapy. The most common cause of acute exacerbation is respiratory tract infection, which can be categorized into mild, moderate, and severe, depending on the treatment required. Exacerbations of COPD are important events in the management of COPD, because they negatively impact health status, rates of hospitalization and readmission, and disease progression.2, 4, 5, 6

N‐acetylcysteine (NAC) is frequently used in patients with COPD as a mucolytic. Besides its mucolytic effects, high‐dose NAC has additional benefits in patients with stable COPD, including improving lung function and reducing exacerbations. The benefits of NAC in COPD are related to its antioxidant properties.7 Taken orally, NAC is deacetylated to cysteine, leading to increased concentrations of reduced glutathione in the plasma and airways.8, 9 Studies on the dose‐dependent effects of NAC in COPD patients showed a high dose of NAC was needed to achieve its antioxidant effects and clinical benefits in COPD patients, whereas a dose of 600 mg once daily was not able to increase glutathione levels.10 According to a study conducted in Hong Kong on patients with stable COPD, 1 year of treatment with high‐dose NAC at 600 mg twice daily improved small airways function in terms of forced expiratory flow from 25% to 75% and forced oscillation technique, and also significantly reduced exacerbation frequency with a decreasing trend in admission rate.11 In a meta‐analysis, patients treated with NAC had significantly and consistently fewer exacerbations of COPD.12

The role of NAC was examined in a Delphi consensus study involving 53 COPD experts from 12 countries.13 Respondents agreed that regular treatment with mucolytic agents could effectively decrease the frequency of exacerbations and the duration of mild‐to‐moderate exacerbations, while delaying the time to first exacerbation and increasing symptom‐free time in COPD patients. Moreover, they concurred that NAC could improve the efficacy of some classes of antibacterial drugs and was effective as a short‐term treatment for the symptoms of acute exacerbations when combined with other drugs. The panel in the Delphi consensus study also approved the doses of NAC with favourable side effect profiles to be recommended for regular use in patients with a bronchitic phenotype.

However, there have been conflicting results regarding the efficacy of NAC for treating acute exacerbation of COPD. A double‐blind, double‐dummy, placebo‐controlled randomized study in 123 patients experiencing an acute exacerbation of COPD suggested treatment with NAC 1200 mg/day could improve biological markers and clinical outcomes.14 However, the primary outcome in this study was the change in inflammatory markers, which are also affected by the cause of the exacerbation. Moreover, changes in inflammatory makers may not have significant clinical and physiological implications. In addition, antimicrobial treatments can also be another cofounding factor. Another small‐scale study on 40 patients found the NAC group showed significant improvements in the mean partial pressure of oxygen (PaO₂) on days 3 and 7, and partial pressure of carbon dioxide (PaCO₂), and oxygen saturation (SaO₂) on day 7; the clinical signs including wheezing and dyspnoea; and the need for nasal oxygen support.15

On the other hand, another double‐blind trial randomly assigned 50 patients with COPD exacerbation to receive NAC (600 mg, twice daily) or placebo for 7 days. They found there were no differences in the rate of change of forced expiratory volume in 1 second (FEV₁), vital capacity, oxygen saturation, breathlessness, or length of hospital stay between the two groups.16, 17, 18 However, this study had a small sample of only 25 subjects in each group and also focused on parameters that might not reflect the situation in COPD acute exacerbation such as FEV₁ and vital capacity, while other important parameters such as cough score, sputum volume, and mortality on discharge were not assessed. Negative results were reported in a placebo‐controlled study,19 which included patients with severe COPD and increased sputum production who were hospitalized for an exacerbation. Subjects were randomized to receive either NAC 200 mg three times daily or placebo in addition to their usual treatment. They found significant improvements in the ease of sputum production, dyspnoea at rest and on exertion, FEV₁, and PaO₂ in both NAC and placebo groups, with no difference between the two groups. The dose of NAC used in this study was below the level needed to affect glutathione levels, which may account for the lack of difference in the observed benefits in these two groups. Despite the potential benefits of NAC in COPD exacerbation, NAC has not been included as an adjunct for the treatment of COPD exacerbation in international guidelines. A possible explanation could be related to the contradicting results from various studies. In the largest scale study conducted so far, the change in inflammatory markers was the primary outcome, whereas the clinical outcomes were the secondary outcomes.14 Other studies that used clinical outcomes as the primary outcome of interest had rather small sample sizes, and these studies showed inconsistent results. A dedicated study focusing on objective clinical and physiological outcomes is urgently needed. As NAC is relatively low cost, readily available, and has a favourable side effect profile as a treatment for COPD exacerbation, it is important to properly assess the clinical benefits of NAC as an adjunct to standard medical treatments to hasten recovery.

Hypotheses

The use of NAC in acute COPD exacerbation can improve physiological parameters, symptoms, lung function, reduce blood inflammatory markers, and length of hospital stay.

Objective

This study will assess the role of NAC in the treatment of acute COPD exacerbation in terms of clinical, physiological, and laboratory parameters, including PaO₂, PaO₂/FiO₂ ratio, PaCO₂, SaO₂, end‐tidal CO₂, length of stay, coughing, wheezing, dyspnoea, need for supplemental oxygen sputum volume, FEV₁, and blood inflammatory markers.

Trial design

Study Type: Interventional

Primary Purpose: Treatment

Study Phase: Phase 3

Interventional Study Model: Parallel Assignment

This study is a double‐blind randomized controlled trial on NAC as an adjunctive treatment for acute COPD exacerbation. The randomization will be done via computer software with half of the patients randomized to receive oral NAC (600 mg twice daily) and half receive placebo, with randomization ratio being 1 to 1. Patients in the two randomized group will be asked to participate in the study for a maximum of 1 week.

Number of Arms: 2

Masking: Double (Participant, Investigator)

Allocation: Randomized

Enrolment: 80 [Anticipated]

Subjects (with justification on sample size)

This clinical trial will be conducted at the Department of Medicine, Queen Mary Hospital. The Division of Respiratory Medicine at Queen Mary Hospital is a tertiary referral centre serving the entire territory and is the major receiving unit for patients with various respiratory diseases (including COPD) in the Hong Kong West Cluster. Based on hospital admission records in the past 12 months, there were on average 77 patients with acute exacerbation of COPD admitted to the general medical ward every month. Potential study subjects will be recruited from general medical and respiratory subspecialty wards based at Queen Mary Hospital. The following eligibility criteria will apply.

Inclusion criteria:

1. Aged 40 years or above, either male or female.

2. Patients who are current or ex‐smokers

   1. Ever‐smoker is defined as having smoked at least one cigarette, pipe, water pipe, cigars, or hand rolled cigarettes a day for 1 or more years.

3. Patients with a pre‐existing diagnosis of COPD admitted to the general medical and respiratory subspecialty wards for acute COPD exacerbation

   1. COPD is defined as dyspnoea and/or chronic productive cough with spirometry confirmation of persistent airflow limitation at FEV1/FVC less than 70%.

   2. COPD acute exacerbation is defined as an acute increase in symptoms (one or more of the following: cough frequency and severity, sputum production, dyspnoea) beyond normal day‐to‐day variations leading to a change in medication.

4. Patients who consent to join this clinical trial

Exclusion criteria:

1. Patients who are on long‐term NAC treatment

2. Patients who are not able to take NAC including drug allergy

3. Patients with other co‐existing respiratory diseases including but not limited to asthma, interstitial lung diseases, and bronchiectasis

4. Patients on non‐invasive or invasive mechanical ventilation where oral medication is not allowed.

5. Patients on long term macrolide treatment

6. Patients on macrolide as antibiotics for COPD exacerbation

Methods

Study design

This is a double‐blind randomized controlled trial on NAC as an adjunctive treatment for acute COPD exacerbation. Eligible subjects with COPD will be identified from either the general medical ward or the respiratory subspecialty ward at the Department of Medicine, Queen Mary Hospital. Details of the study will be explained to potential subjects by the PI or his designee before obtaining written informed consent. COPD exacerbation was defined as an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days.25, 26 Mild exacerbations were defined in patients treated with short acting bronchodilators (SABD) only. Moderate exacerbations were defined in patients who were treated with SABDs and oral corticosteroids ± antibiotics. Severe exacerbations were defined in patients that required hospitalizations or visit to the emergency room.25 At the first visit, detailed history taking, physical examination, and baseline assessments (body weight, body height, body‐mass index, complete blood count, liver function test, renal function test, arterial blood gas, and chest x‐ray) will be performed. Baseline assessments will include PaO₂, PaO₂/FiO₂ ratio, PaCO₂, 24‐hour sputum volume, SaO₂, end‐tidal CO₂, cough score by Leicester cough questionnaire (LCQ), COPD Assessment Test (CAT) at 24 h after admission, grade of wheeze, dyspnoea by mMRC Dyspnoea Scale, and lung function test by the portable spirometer. Blood inflammatory markers including white cell count, neutrophil count, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), and high‐sensitivity CRP (hs‐CRP) will also be measured, total 20 mL of blood will be taken. The blood tests arranged for the patients are the basic blood tests for clinical management of COPD exacerbation and it does not involve extra blood testing for the patients. Patients in both treatment and placebo groups will receive identical standard of care for COPD acute exacerbation including oral prednisolone 30 mg daily for 1‐week (With concomitant pantoprazole 40 mg daily [if not on proton pump inhibitor before the admission] and potassium chloride 600 mg twice daily[Omitted if blood potassium level is above upper limit of normal]), inhaled salbutamol four puffs every 4 h for 1 week, and antibiotics with oral Amoxicillin/Clavulanic acid 1 gram twice daily according to the standard treatment order form. Alternative antibiotics can be used if patients have allergy or contraindications, and it will be decided by the PI or Co‐I. The usual inhalers and oral medications for COPD will be continued. The patients will also be prescribed with the necessary medications for symptomatic relief. For mucolytics, both patients in the treatment and placebo group will be prescribed with mucolytics that do not contain NAC such as bromhexine, cyclidrol or ambroxol if needed. Patients recruited into the study will be taken to the Respiratory ward in Queen Mary Hospital for further care. Subjects fulfilling the selection criteria will be randomized in a 1:1 ratio to receive either oral NAC at 600 mg twice daily or placebo (identical appearance and similar taste) twice daily for 7 days. Randomization will be done by computer program. Randomization will be stratified according to disease severity at enrolment. Mild disease is defined as those not needing supplemental oxygen, whereas moderate disease is defined as those who need supplemental oxygen but not ventilator support. The NAC or placebo treatments will be delivered to the ward by the Pharmacy Unit after the designated drug prescription form has been signed by the Principal Investigator [PI]/Co‐Investigators [Co‐Is]. The NAC or placebo treatments will then be given by ward nurses who will be blinded to the treatment arm. A specific item code for NAC or placebo will be prepared by the pharmacy department of Queen Mary Hospital. Placebo with identical taste and appearance will be prepared by Zambon Pharma. Arterial blood gas will be checked on days 1 and 7 for PaO₂ and PaCO₂ value, as well as to calculate the PaO₂/FiO₂ ratio. The 24‐h sputum volume, SaO₂, end tidal CO₂, LCQ score, grade of wheeze, CAT score, and dyspnoea by mMRC Dyspnoea Scale will be carried out by blinded research assistants, the PI, or Co‐Is and repeated on days 4 and 7. Blood inflammatory markers including white cell count, neutrophil count, ESR, CRP, and hs‐CRP will be measured on days 4 and 7. Lung function test by portable spirometer will be performed on days 1, 4 and 7. Time to wean off supplemental oxygen, length of hospital stay, and 28‐ and 90‐day mortality will be recorded.

Subgroup analysis will be performed on patients with COPD exacerbation with different severity.

For patients who have hospital stay less than 7 days, the day 4 and 7 assessment will be performed in out‐patient setting with ward follow up arranged in B6 ward for them. The NAC and placebo, together with other treatment for COPD exacerbation will be provided to the patients upon discharge. As such, this would not lead to any lengthening of the length of stay.

Any adverse events will be recorded according to the Common Terminology Criteria for Adverse Events [CTCAE] version 5.

Data processing and analysis

For the primary endpoint of interest, that is, the difference in mean PaO₂ on day 7 of treatment, it will be compared among the two treatment groups by two‐sample t‐test. The change in the measures (PaO₂/FiO₂, PaCO₂, sputum volume, FEV₁, SaO₂, LCQ score, CAT score, end tidal CO₂, grade of wheeze mMRC Dyspnoea scale, blood inflammatory markers, time to wean off supplemental oxygen, and 28‐ and 90‐day mortality) will be tested using a two‐sample t‐test. For results that do not follow normal distribution, non‐parametric Wilcoxon signed‐rank test will be used instead. Clinical characteristics of patients will be tabulated. For categorical outcomes, they will be compared by Chi‐square (χ²) test if they have normal distribution while Mann–Whitney U will be used if the outcomes do not follow normal distribution. The demographic and clinical data will be described in actual frequency or mean ± SD, or median and interquartile range where appropriate. Baseline demographic and clinical data will be compared between two treatment groups by independent t‐test or non‐parametric tests where appropriate. Multiple linear regression modelling will be used to take into account potential confounders (age, gender etc.). A p‐value of <0.05 will be considered statistically significant. All the statistical analyses will be performed using the latest version of SPSS statistical package.

Potential hazards to subjects in the study

The subjects will need extra blood taking for arterial blood gas on day 7. The reported major complication rate from arterial puncture for arterial blood gas within 7 days was 0.14%,27 which include embolisms or thrombosis, aneurysms, nerve damage and arteriovenous fistulas. In general, arterial puncture for arterial blood gas is considered to be a low‐risk procedure with major complication rate of 0.14% only.

Confidentiality and use of results

The demographic and clinical data collected from study subjects will be stored securely at the study site, with access by the principal investigator or designated research staff. All collected data will be stored in computers locked in PI's office. All data files will be encrypted and confidential information (e.g., Hong Kong Identification Card (HKID) numbers) will be replaced with study numbers in the dataset. These data will only be used for the study as outlined in this protocol and individual patient's identity will be removed after completion of statistical analyses. No personal particulars will be included in all future scientific reports generated from this study. All data files will be deleted 5 years after completion of the study. We will ensure the compliance with ICH‐GCP.

Data monitoring

The data monitoring committee consists of the co‐authors of this study protocol, who are all independent from the sponsor of the study and have no competing interests. The members of the data monitoring committee also are not involved in the subject recruitment and assessment. The trial will be stopped once the planned subject number was reached, no adverse events or unintended effects are expected. The data monitoring committee will also monitor study safety outcomes.

Trial status at submission

Recruiting; Actual study start date: 2023‐09‐18; Estimated recruitment completion date: 2024‐12‐31.

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