Comparative Effectiveness of Roflumilast and Azithromycin in Reducing Exacerbations in Severe Chronic Obstructive Pulmonary Disease ( COPD ) Patients With Chronic Bronchitis Phenotype

This single-center, randomized controlled trial (RCT) will compare roflumilast and azithromycin as add-on therapies in 70 participants with severe Chronic Obstructive Pulmonary Disease (COPD) and frequent exacerbations. Participants will receive either roflumilast 500 micrograms (µg) orally once daily or azithromycin 250 milligrams (mg) orally once daily for six months, in addition to standard inhaled chronic obstructive pulmonary disease(COPD) therapy. The study will evaluate the comparative effectiveness of these treatments in reducing the frequency and severity of chronic obstructive pulmonary disease (COPD) exacerbations and improving clinical outcomes, including forced expiratory volume in one second (FEV₁), modified Medical Research Council (mMRC) dyspnea score, hospitalization rates, treatment adherence, and safety. The findings are expected to provide local evidence to inform the selection of appropriate add-on therapy for patients with severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations.

Protocol Description Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality worldwide and is characterized by persistent respiratory symptoms, progressive airflow limitation, and recurrent acute exacerbations. Frequent exacerbations are associated with accelerated decline in lung function, impaired quality of life, increased hospitalization rates, higher healthcare costs, and increased mortality. Despite optimal inhaled therapy, including long-acting bronchodilators with or without inhaled corticosteroids, many patients with severe chronic obstructive pulmonary disease (COPD) continue to experience recurrent exacerbations, underscoring the need for effective add-on therapies.

Roflumilast, an oral selective phosphodiesterase-4 (PDE-4) inhibitor, reduces airway inflammation by increasing intracellular cyclic adenosine monophosphate (cAMP) levels. It has been shown to reduce the frequency of exacerbations, particularly in participants with severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. Azithromycin, a macrolide antibiotic, possesses anti-inflammatory and immunomodulatory properties in addition to its antimicrobial effects and has also demonstrated efficacy in reducing chronic obstructive pulmonary disease (COPD )exacerbations.

However, limited direct comparative evidence exists regarding the relative effectiveness and safety of roflumilast and azithromycin, particularly among patients with severe COPD in the Pakistani population. Accordingly, this study is designed to compare these two therapies as add-on treatments in patients who continue to experience frequent exacerbations despite standard inhaled therapy.

This single-center, randomized controlled trial will enroll 70 eligible patients with severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations using non-probability consecutive sampling. Participants will be randomly assigned in a 1:1 ratio to two treatment groups. One group will receive roflumilast 500 micrograms (µg) orally once daily, while the other will receive azithromycin 250 milligrams (mg) orally once daily. Both treatments will be administered in addition to standard chronic obstructive pulmonary disease (COPD) therapy for six months.

At baseline, participants will undergo a comprehensive clinical assessment, including evaluation of demographic characteristics, smoking history, chronic obstructive pulmonary disease (COPD) history, exacerbation history, co morbidities, medication history, spirometry, and symptom burden using the modified Medical Research Council (mMRC) dyspnea scale. Post-bronchodilator forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) will be recorded in accordance with standard spirometric procedures.

Participants will be followed at scheduled intervals throughout the six-month treatment period. Follow-up assessments will include the occurrence and severity of COPD exacerbations, hospitalization, changes in post-bronchodilator FEV₁, mMRC dyspnea score, treatment adherence, and adverse drug events. Medication adherence will be assessed using study medication records and participant-reported follow-up information.

The primary outcome will be the reduction in the frequency and severity of chronic obstructive pulmonary disease (COPD) exacerbations during the six-month follow-up period.

Secondary outcomes will include:

• Change in post-bronchodilator forced expiratory volume in one second (FEV₁).
• Change in modified Medical Research Council (mMRC) dyspnea score.
• Hospitalization rate due to chronic obstructive pulmonary disease (COPD) exacerbations.
• Time to first chronic obstructive pulmonary disease (COPD) exacerbation.
• Treatment adherence.
• Frequency and type of adverse drug events.
• Treatment discontinuation due to adverse effects. Data will be analyzed using the Statistical Package for the Social Sciences (SPSS), version 27. Continuous variables will be expressed as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. Categorical variables will be presented as frequencies and percentages.

The independent-samples t-test will be used to compare normally distributed continuous variables between the two treatment groups. The Mann-Whitney U test will be used for non-normally distributed continuous variables. The chi-square test or Fisher's exact test will be used to compare categorical variables, as appropriate. A p-value of ≤0.05 will be considered statistically significant.

Where appropriate, stratified analyses will be conducted to assess the potential influence of important baseline characteristics and confounding factors, including age, sex, smoking status, baseline forced expiratory volume in one second (FEV₁), baseline forced expiratory volume in one second/forced vital capacity (FEV₁/FVC) ratio, and comorbidities.

The study is expected to provide local evidence regarding the comparative effectiveness, tolerability, and safety of roflumilast and azithromycin as add-on therapies in participants with severe chronic obstructive pulmonary disease (COPD)and frequent exacerbations. The findings may assist clinicians in selecting an appropriate additional pharmacological treatment for participants who continue to experience exacerbations despite standard inhaled therapy.

The Results section will present findings obtained after completion of the six-month follow-up period. Baseline demographic and clinical characteristics will be compared between the roflumilast and azithromycin treatment groups to assess the comparability of the randomized groups.

The primary outcome will be reported as the frequency and severity of Chronic Obstructive Pulmonary Disease (COPD) exacerbations occurring during the six-month follow-up period. The number of exacerbations, the proportion of participants experiencing at least one exacerbation, and exacerbation severity will be compared between the two treatment groups.

Secondary outcomes will include changes in forced expiratory volume in one second (FEV₁), modified Medical Research Council (mMRC) dyspnea score, hospitalization rate, time to first chronic obstructive pulmonary disease (COPD) exacerbation, medication adherence, and adverse drug events.

Spirometric outcomes will be presented using post-bronchodilator forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC). Changes from baseline to the end of the six-month treatment period will be compared between the two treatment groups.

Treatment adherence and adverse drug events will also be reported for both groups. Adverse events will be categorized according to type, frequency, severity, and whether they resulted in treatment discontinuation.

Statistical analysis will be performed using the Statistical Package for the Social Sciences (SPSS), version 27. Continuous variables will be presented as mean ± standard deviation (SD) or median with interquartile range (IQR), according to the distribution of the data. Categorical variables will be presented as frequencies and percentages. Appropriate statistical tests, including the independent-samples t-test, Mann-Whitney U test, chi-square test, and Fisher's exact test, will be applied according to the type and distribution of the data. A p-value of ≤0.05 will be considered statistically significant.

The final results will determine whether roflumilast or azithromycin provides greater benefit in reducing chronic obstructive pulmonary disease (COPD )exacerbations and improving clinical outcomes among patients with severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations receiving standard inhaled therapy.