ORIGINAL ARTICLE

https://doi.org/10.5005/jp-journals-11010-1065
Indian Journal of Respiratory Care
Volume 12 | Issue 3 | Year 2023

A Comparative Study to Assess Efficacy and Safety of NAC Combination and NAC in Patients of Productive Cough with Acute Bronchitis

Harsh J Shah¹ https://orcid.org/0009-0008-6865-1770, Ankit Singh², Jacky Pariyani³, Kalyani V Shinde⁴, Paarth Kumar⁵ https://orcid.org/0009-0006-1056-9905

^1,3–5Department of Medical Affairs, La Renon Healthcare Pvt Ltd, Gujarat, Ahmedabad, India

²Department of Business Development, La Renon Healthcare Pvt Ltd, Gujarat, Ahmedabad, India

Corresponding Author: Harsh J Shah, Department of Medical Affairs, La Renon Healthcare Pvt Ltd, Gujarat, Ahmedabad, India, Phone: +91 9879540270, e-mail: HarshJayendrashah23@gmail.com

Received on: 12 May 2023; Accepted on: 25 September 2023; Published on: 30 October 2023

ABSTRACT

Background: Chronic obstructive pulmonary disease (COPD) is characterized by the impact of bad air, often progressive and irreversible, caused by a combination of different lung diseases, damage to the lungs, and emphysema, followed by inhalation of bad air and gases, especially smoke, causes, and often affects lung disease with many differences.

By adding lactoferrin along with N-acetylcysteine (NAC), it targets nuclear factor-κB (NF-κB), which is responsible for inflammatory responses. This combination of NAC 600 + lactoferrin 50 mg offers synergistic effects and reduces mucus hypersecretion (as a mucolytic agent).

Objective: This study was a randomized, open-label, actively controlled, prospective, single-center, two-arm, parallel to assess the efficacy, safety, and tolerability of the combination of NAC 600 + lactoferrin 50 mg against NAC 600 mg in the symptomatic treatment of patients suffering from productive cough associated with acute bronchitis.

Materials and methods: The study was conducted under a qualified investigator at a single center in India. To assess the primary efficacy of the investigational products, assessment through a modified cough and sputum relief questionnaire was evaluated at baseline days 0, 3, 5, and 8. Secondary efficacy was evaluated through a 7-point Likert scale, bronchial severity score (BSS), and global clinical impression of improvement or change (CGIC); secondary safety endpoints were measured through adverse events (AEs) or serious AEs (SAEs) collected during the study.

Results: It was observed that the combination of NAC and lactoferrin showed better primary and secondary efficacy results with respect to the treatment of acute bronchitis. The rate of reduction in the severity of acute bronchitis and improvement of breathing condition/general well-being is also showing better results in combination products compared to NAC 600 mg. SAEs were not reported during the conduct of the study.

Conclusion: Based on the study results/data, it can be concluded that the combination of NAC and Lactoferrin shows better efficacy results with no linked AEs with respect to the treatment of acute bronchitis compared to single treatment. However, long-term studies will be done to evaluate the long-term effectiveness of the combination of NAC and lactoferrin.

How to cite this article: Shah HJ, Singh A, Pariyani J, et al. A Comparative Study to Assess Efficacy and Safety of NAC Combination and NAC in Patients of Productive Cough with Acute Bronchitis. Indian J Respir Care 2023;12(3):254–258.

Source of support: Nil

Conflict of interest: None

Keywords: Bronchitis, Cough, Lactoferrin, Respiratory

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is usually characterized by progressive and irreversible COPD of the small airways and emphysema as a result of inhalation of bad air and gases (especially cigarette smoke), causes lung inflammation, and is often associated with many diseases, several comorbidities are frequently associated.

Mucus hypersecretion is an important phenotype in COPD. Disease exacerbation is associated with a rapid decline in forced expiratory volume and inflammatory cell infiltration. Therefore, sputum removal and sterile care are important in COPD. In addition, COPD is associated with oxidative stress, which causes inactivation of antiproteases, airspace epithelial damage, mucus hypersecretion, neutrophil influx into the lungs, activation of transcription factors, and increased gene expression of proinflammatory mediators.¹^,²

In addition to effective anti-inflammatory and antioxidant properties, drugs with mucolytic activity may be effective in the treatment of COPD.

N-acetylcysteine (NAC) is a potent mucolytic agent that reduces mucus viscosity and elasticity. In addition to mucolytic activity, NAC has been shown to be a potent antioxidant and free radical scavenger. NAC, when given orally, has been shown to protect the lungs from the damage of air pollution and cigarette smoking.

Currently, available treatment options contain NAC monotherapy or combination with acebrophylline (like bronchodilator), but NAC, along with a strong anti-inflammatory agent combination, lacks bronchodilation and anti-inflammatory action, which can mitigate the long-term mucolytic and inflammation problems in COPD.³^,⁴

RATIONALE OF NAC + LACTOFERRIN COMBINATION

By adding lactoferrin along with NAC, it targets nuclear factor-κB (NF-κB), which is responsible for inflammatory responses. NAC inhibits oxidative stress by acting directly as a reactive oxygen species scavenger and altering the cellular redox state.⁵ In turn, this may affect the activation of nuclear factor-κB (NF-κB) and control the inflammatory response. This may directly or indirectly affect mucin 5AC, oligomeric mucus/gel-forming activity and, thus, mucus hypersecretion. Lactoferrin activates NF-κB, which inhibits the release of inflammatory substances.

This combination may offer synergistic effects and reduce mucus hypersecretion (as a mucolytic agent). In the proposed study, we have assessed the efficacy, safety, and tolerability of a combination of NAC 600 mg + lactoferrin 50 mg against NAC 600 mg in the symptomatic treatment of patients suffering from productive cough associated with acute bronchitis.

Patients with coughs often come to doctors working in primary and secondary care.⁶^,⁷ An acute cough often occurs after an upper respiratory tract infection and acute bronchitis; although they can be devastating at first, they are usually self-limiting and rarely require significant medical intervention. Chronic cough is often a major symptom of many important chronic respiratory diseases, but it can be the only symptom of many extrapulmonary situations, like gastrointestinal disease and upper airway. Also, with a flawless diagnosis, it is difficult to control coughing and can reduce the quality of life of the patients.⁸^,⁹ This trial is to establish the safety, efficacy, and tolerability of a combination of NAC 600 mg + lactoferrin 50 mg against NAC 600 mg in the symptomatic treatment of patients suffering from productive cough associated with acute bronchitis.

MATERIALS AND METHODS

This randomized study was an open-label, actively controlled, prospective, single-center, two-arm, and parallel study to evaluate the efficacy, safety, and tolerability of a combination of NAC 600 mg + lactoferrin 50 mg against NAC 600 mg in the symptomatic treatment of patients suffering from productive cough associated with acute bronchitis. The study was conducted by a qualified investigator at a single center in India, and it was initiated after the written EC approval. After confirming eligibility criteria, 60 patients out of 65 subjects (five subject screen failure) suffering from productive cough associated with acute bronchitis were enrolled in a 1:1 order.

The reference group of 30 subjects received NAC 600 mg by mouth (PO), twice a day (BID).
A test group of 30 subjects received a combination of NAC 600 mg + lactoferrin 50 mg PO, BID.

All 60 enrolled subjects were prescribed and dispensed study medication on randomization/enrollment (day 0), and subjects were instructed to take the medication on day 1 and to use it for 7 days. Subjects were followed up on days 3, 5, and 8. A complete physical examination was performed at screening/baseline. At subsequent visits, only partial physical examination was done that included ENT, heart, lungs, general appearance, and lymph nodes. The test of urine pregnancy was performed in women with child-bearing potential.

Assessment of the measurement of breathlessness on a 7-point Likert scale, bronchial severity score (BSS), and assessment through a modified cough and sputum relief questionnaire was evaluated at days 0 (baseline), 3, 5, and 8.

Clinical and Safety Evaluation

Assessment of the Measurement of Breathlessness on a 7-point Likert scale

Breathlessness is described as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. Improvement in breathlessness is measured over a 7-point Likert scale.

Assessment of Modified Questionnaire for Ease of Cough and Sputum Clearance

the severity of cough and sputum clearance was measured using the modified questionnaire for ease of cough and sputum clearance.

Assessment of Clinical Global Impression of Improvement or Change Scale (CGIC)

At the screening/baseline/randomization visit (day 0) and end of the study (EOS), that is, day 8 (EOS), all patients were asked to grade their impression of improvement or change in their condition using the CGIC scale, which is a 7-point rated scale.

Assessment of Change in Mean BSS

Change in the total score of the BSS was evaluated as a secondary endpoint through a standardized and validated questionnaire to assess the severity of bronchitis. The BSS comprises the following five symptoms typical for acute bronchitis: cough, sputum production, cough-induced chest pain, rales on auscultation, and dyspnea. Each symptom was assessed according to a 5-point Likert scale: 0 = absent, 1 = mild, 2 = moderate, 3 = severe and 4 = very severe. The points allocated to each of the symptoms were added to make the total score; therefore, the total varies between 0 and 20 points. In addition to the total score, the individual scores of each symptom were assessed in the study. Complete recovery was defined as a BSS total score of ≤3.

Safety evaluation was based on adverse events (AE), vitals assessment (pulse rate, systolic and diastolic blood pressure (seated), body temperature, and respiratory rate), ECG, and physical examination (timeframe: baseline with days 3, 5, and 8).

RESULTS

A total of 65 subjects were screened, and only the 60 who were enrolled in this study received at least one dose of the study product and were included in the safety group and mITT population.

Demographic Details

Out of 60, there were 19 females (eight in the test and 11 in the reference group) and 41 males (22 in the test and 19 in the reference group).

Primary Efficacy Endpoint

The severity of cough and sputum clearance was measured using a modified questionnaire to assess the ease of coughing and sputum allowance. Analysis was performed using a two-sided test at α, 0.05 (95% confidence interval).

Change in ease of coughing and sputum clearance is assessed over five multiple-choice questions. These multiple-choice questions rate the frequency, severity, or discomfort over a 1–5 scale in decreasing condition order.

Table 1 clearly represents that at each point of the questionnaire, there is a statistically significant difference between the baseline and EOS. Also, the subject’s condition improved at each point of the questionnaire from baseline to the EOS visit. Hence, this change represents the improvement in condition at each point.

**Table 1:** Comparison between treatment groups in ease of cough and sputum clearance from baseline to end of treatment
Parameter	Reduction from baseline to EOS; mean ± standard deviation (SD) (test product)	Reduction from baseline to EOS; mean ± SD (reference product)
How frequently are you coughing today?	3.133 ± 0.346	2.133 ± 0.571
How repeatedly did you cough last night?	3.967 ± 0.183	2.900 ± 0.403
How bad were your cough episodes on a typical day during the past week?	3.000 ± 0.830	1.967 ± 0.183
How easy is it to cough up phlegm today?	2.967 ± 0.809	1.967 ± 0.183
Are you feeling chest tight or uncomfortable today?	3.000 ± 0.910	1.967 ± 0.183

As per Table 1, the improvement from baseline to EOS visit over coughing frequency in a day for the test (3.133 ± 0.346) product is more than the reference product (2.133 ± 0.571). Also, the improvement from baseline to end of study visit over coughing frequency last night for the test (3.967 ± 0.183) is more than the reference product (2.900 ± 0.403). Hence, the improvement in the subject’s cough frequency condition for the test product is greater than that of the reference product.

Improvement from baseline to EOS visit over “cough severity on arising and throughout the day” for the test product (3.000 ± 0.830) is more than the reference product (1.967 ± 0.183). Over the scale of ease of getting up sputum during the day, the condition improvement in the test group (2.967 ± 0.809) is better than the reference group (1.967 ± 0.183). Over the scale of “the discomfort in the chest, tightness and/or congestion on arising and all over the day,” the condition improvement in the test group is 3.000 ± 0.910, and in the reference group is 1.967 ± 0.183, which shows better result in the test group for the same category.

After assessing both the products over each scale for ease of coughing and sputum clearance over a modified questionnaire (5-point), we can say that the test product results are better than the reference product.

Secondary Efficacy Endpoints

Improvement in Breathlessness

Breathlessness condition is measured through a 7-point Likert scale on visits 1, 2, 3, and 4. Here, we are analyzing the improvement in the breathlessness of study subjects from baseline to the EOS visit by comparing the average scale for the test and reference product.

Table 2 indicates that there is a statistically significant difference between baseline and EOS values with respect to the 7-point Likert scale (i.e., p-value of <0.05).

**Table 2:** Improvement in breathlessness (7-point Likert scale)
Group	Baseline visit mean (SD)	EOS visit mean (SD)	Mean change from baseline to EOS mean (SD)	p-value
Test group	4.23 (0.430)	1.10 (0.305)	3.133 (0.507)	0.0001
Reference group	4.03 (0.320)	2.20 (0.407)	1.833 (0.379)	0.0001

The average breathing condition of subjects at the EOS over the Likert scale for test and reference product is 1.10 ± 0.305 (i.e., sight shortness of breath > 1.10 ± 0.305 > not short of breath at all) and 2.20 ± 0.407 (i.e., specific shortness of breath > 2.20 ± 0.407 > slight shortness of breath), respectively. In contrast, the average breathing condition of study participants at baseline visit of the test and reference group is 4.23 ± 0.430 and 4.03 ± 0.320, respectively, which is either the condition of moderate shortness of breath or quite a bit short of breath. The improvement in breathlessness for a combination of NAC 600 mg + lactoferrin 50 mg is 3.133 ± 0.507, and for NAC 600 mg is 1.833 ± 0.379, which clearly represents a better result in the test group (NAC 600 mg + lactoferrin 50 mg).

Change in Mean BSS

Bronchial severity score (BSS) contains six criteria over the severity of acute bronchitis, that is, measured over each visit of the study.

Here, we are assessing the change in bronchial severity of study subjects over baseline and EOS visits for the test and reference products.

This figure compares the change of the population over different bronchial severity scales from baseline to end of treatment for test and reference products.

Study data shows that the maximum study population at the baseline visit is suffering from either mild or moderate acute bronchitis condition in each group. Figure 1 shows that the number of patients is decreased for moderate (by 23% test product and 10% reference product) and mild (by 73.33% test product and 50% Reference product) conditions of acute bronchitis. In contrast, the number of patients is increased with unlikely (3.33% test product and 13.33% reference product) and no (93.33% test product and 46.67% reference product) acute bronchitis condition. Table 3 describes the change of population over different bronchial severity scales from baseline to end of treatment in test and reference products, and there is no subject who still has the acute bronchitis condition at the end of the experimental study group, which shows each and every patient condition is improved for test product. Also, there is a statistically significant relationship between baseline and EOS values with respect to the bronchial severity scale (i.e., p-value of <0.05).

**Table 3:** Change of population over different bronchial severity scales from baseline to end of treatment (test and reference products)
Total severity scale and clinical interpretation	Baseline visit N = 30 n (%)		EOS visit N = 30 n (%)		Chi-square value, degree of freedom		p-value
	Test	Reference	Test	Reference	Test	Reference	Test	Reference
0: not acute bronchitis	0 (0.0%)	0 (0.0%)	28 (93.3%)	14 (46.7%)	57.333, 3	26.933, 3	0.0001	0.0001
1–2: acute bronchitis unlikely	1 (3.3%)	0 (0.0%)	2 (6.7%)	4 (13.3%)
2–7: mild acute bronchitis	22 (73.3%)	21 (70.0%)	0 (0.0%)	6 (20.0%)
8–12: moderate acute bronchitis	7 (23.3%)	9 (30.0%)	0 (0.0%)	6 (20.0%)
13–17: severe acute bronchitis	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)
18–20: very severe acute bronchitis	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)

Fig. 1: Comparison in change of population over different bronchial severity scales from baseline to end of treatment

Also, the percentage of subjects with no acute bronchitis condition for the test product is more than that of the reference product. Hence, the recovery rate for the test product (NAC 600 mg + lactoferrin 50 mg) is more than the reference product (NAC 600 mg).

General Well-being Changes Shown in Patients

Change in the patient’s general well-being is assessed through the CGIC at the screening/baseline/randomization visit (day 0) and EOS that is, day 8. Through this scale, subjects measured their impression of improvement in this study. Here, we are calculating how much of the population of the study falls under which criteria of the CGIC scale over baseline and EOS visit for test and reference product, and by using this data, we will analyze the change in general well-being of the patients.

Table 4 illustrates a statistically significant relationship between baseline and EOS values for test and reference products with respect to the CGIC scale (i.e., p-value <0.05 for both).

**Table 4:** Change of population over seven different scales of clinical global impression of improvement from baseline to end of treatment (test and reference products)
CGIC 7-point rated scale	Baseline visit N = 30 n (%)		EOS visit N = 30 n (%)		Chi-square value, degree of freedom		p-value
	Test	Reference	Test	Reference	Test	Reference	Test	Reference
0 = not assessed	0 (0.0%)	0 (0.0%)	0 (0.0%)	1 (3.3%)	60.000, 3	60.000, 1	0.0001	0.0001
1 = very much improved	0 (0.0%)	0 (0.0%)	30 (100.0%)	16 (53.3%)
2 = greatly improved	0 (0.0%)	0 (0.0%)	0 (0.0%)	13 (43.3%)
3 = slightly improved	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)
4 = no change	30 (100.0%)	30 (100.0%)	0 (0.0%)	0 (0.0%)
5 = minimally worsened	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)
6 = much worsened	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)
7 = very much worsened	0 (0.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)

Also, the table data described that 100% of the study population (both groups) rated his/her impression of improvement on a scale of 4, i.e., no change at the baseline visit. At the EOS, subjects realized that their general well-being had improved from the baseline visit, and they rated their impression of improvement as 1 (very much improved) or 2 (much improved).

Table 4 shows that the 100% population of the test and reference groups improved their general well-being and positively rated their impression of change. There is no subject who has assessed his/her general well-being as minimally improved at the EOS visit. The number of patients with much improved (43.33% reference and 0% test products) and very much improved (53.33% reference and 100% test products) conditions increased at the EOS visit. Table 4 clearly shows that 100% of the study population of the test group assessed his/her general well-being as “very much improved.” Hence, the improvement in the patient’s general well-being for the test product is greater than that of the reference product.

Safety Results

Adverse Events (AEs) and Serious Adverse Events (SAEs)

There were only two AEs reported, one in the test group (headache) and the second in the reference group (vomiting). Further, no AE has any causal relationship with IMP.

Serious adverse events (SAEs) were not reported during the study conduct.

DISCUSSION

Acute bronchitis is usually caused by a virus, such as the influenza (flu) virus. But many other viruses also can be a cause of acute bronchitis.¹⁰ About 5% of adults have an episode of acute bronchitis each year. An estimated 90% of these seek medical advice for the same. Approximately 95% of acute bronchitis in healthy adults is secondary to viruses. It can sometimes be caused by allergens, irritants, and bacteria. Irritants include smoke inhalation, polluted air inhalation, and dust, among others.¹¹

Individuals afflicted by acute bronchitis commonly experience symptoms including productive cough, malaise, struggling breathing, and wheezing. Therefore, patients diagnosed with acute bronchitis primarily require symptomatic treatment to address their cough.

The main goal of treatment is to reduce symptoms, but it is also important to improve the patient’s work and quality of life. Research shows that despite aggressive treatment for bronchitis, many patients who come to the emergency room develop recurrent symptoms that require hospitalization.¹²

N-acetylcysteine (NAC) is one of the available and most common medications for treating patients who are suffering from acute bronchitis. NAC serves as both a mucolytic and antioxidant agent, with the potential to impact various inflammatory pathways. Functioning as a mucolytic, it has the capability to reduce sputum viscosity, facilitating bronchial clearance and consequently reducing dyspnea, thereby enhancing overall lung function.¹³

Lactoferrin has antibacterial properties (bactericide, fungicide) and is part of the innate defense, mainly of mucous membranes. Lactoferrin, in particular, provides antibacterial properties to human infants. Many studies have shown that lactoferrin has anti-inflammatory properties in vitro that cause infectious diseases such as the common cold, flu, stomach illness, gastroenteritis, summer cold, and herpes virus, where lactoferrin usually prevents the virus from attaching to the brain.¹⁴

By adding lactoferrin along with NAC and using the same as a combination, the patient’s coughing condition improved over the parameters of cough frequency, severity, ease of cough and sputum clearance, and chest discomfort more than the single NAC. The rate of reduction of cough severity for the combination group of NAC 600 mg + lactoferrin 50 mg is more than the NAC 600 mg group.

The study data demonstrated that:

Reduction in severity, frequency, discomfort in cough-up sputum and chest tightness, which is assessed for ease of coughing and sputum clearance by the modified questionnaire for a combination of NAC 600 mg + lactoferrin 50 mg is statistically significant and more than NAC 600 mg from baseline to EOS visit.
Improvement in breathing condition over a 7-point Likert scale for the combination of NAC 600 mg + lactoferrin 50 mg is more than NAC 600 mg.
Reduction in severity of acute bronchitis over the BSS for a combination of NAC 600 mg + lactoferrin 50 mg is more than NAC 600 mg from baseline to EOS visit.
Improvement in general well-being of the patients for the combination of NAC 600 mg + lactoferrin 50 mg is more than NAC 600 mg, which is assessed by the CGIC from the starting study to the end of study visit.

Limitations of the Study

Since this was a small-scale investigator-initiated study, sample size calculation was not done. Therefore, a large-scale study is required to comprehensively assess the overall efficacy and safety of the product.
As this was a small-scale, single-centric investigator-initiated study, recruitment was challenging, and the duration seemed to be long for the investigator.

CONCLUSION AND CLINICAL SIGNIFICANCE

Based on the study results/ data, it can be concluded that the combination of NAC and lactoferrin shows better efficacy results with no linked AEs with respect to the treatment of acute bronchitis compared to a single treatment. However, to assess the long-term efficiency of the combination of NAC and lactoferrin, a long-duration study can be performed.

ORCID

Harsh J Shah https://orcid.org/0009-0008-6865-1770

Paarth Kumar https://orcid.org/0009-0006-1056-9905

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