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 andazithromycin as add‐on therapies in 70 participants with severe Chronic ObstructivePulmonary Disease (COPD) and frequent exacerbations. Participants will receive eitherroflumilast 500 micrograms (µg) orally once daily or azithromycin 250 milligrams (mg)orally once daily for six months, in addition to standard inhaled chronic obstructivepulmonary disease(COPD) therapy. The study will evaluate the comparative effectiveness ofthese treatments in reducing the frequency and severity of chronic obstructive pulmonarydisease (COPD) exacerbations and improving clinical outcomes, including forced expiratoryvolume in one second (FEV₁), modified Medical Research Council (mMRC) dyspnea score,hospitalization rates, treatment adherence, and safety. The findings are expected toprovide local evidence to inform the selection of appropriate add‐on therapy for patientswith severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations.Protocol Description Chronic Obstructive Pulmonary Disease (COPD) is a major cause ofmorbidity and mortality worldwide and is characterized by persistent respiratorysymptoms, progressive airflow limitation, and recurrent acute exacerbations. Frequentexacerbations are associated with accelerated decline in lung function, impaired qualityof life, increased hospitalization rates, higher healthcare costs, and increasedmortality. Despite optimal inhaled therapy, including long‐acting bronchodilators with orwithout inhaled corticosteroids, many patients with severe chronic obstructive pulmonarydisease (COPD) continue to experience recurrent exacerbations, underscoring the need foreffective add‐on therapies.Roflumilast, an oral selective phosphodiesterase‐4 (PDE‐4) inhibitor, reduces airwayinflammation by increasing intracellular cyclic adenosine monophosphate (cAMP) levels. Ithas been shown to reduce the frequency of exacerbations, particularly in participantswith severe chronic obstructive pulmonary disease (COPD) associated with chronicbronchitis and a history of frequent exacerbations. Azithromycin, a macrolide antibiotic,possesses anti‐inflammatory and immunomodulatory properties in addition to itsantimicrobial effects and has also demonstrated efficacy in reducing chronic obstructivepulmonary disease (COPD )exacerbations.However, limited direct comparative evidence exists regarding the relative effectivenessand safety of roflumilast and azithromycin, particularly among patients with severe COPDin the Pakistani population. Accordingly, this study is designed to compare these twotherapies as add‐on treatments in patients who continue to experience frequentexacerbations despite standard inhaled therapy.This single‐center, randomized controlled trial will enroll 70 eligible patients withsevere chronic obstructive pulmonary disease (COPD) and frequent exacerbations usingnon‐probability consecutive sampling. Participants will be randomly assigned in a 1:1ratio to two treatment groups. One group will receive roflumilast 500 micrograms (µg)orally once daily, while the other will receive azithromycin 250 milligrams (mg) orallyonce daily. Both treatments will be administered in addition to standard chronicobstructive pulmonary disease (COPD) therapy for six months.At baseline, participants will undergo a comprehensive clinical assessment, includingevaluation of demographic characteristics, smoking history, chronic obstructive pulmonarydisease (COPD) history, exacerbation history, co morbidities, medication history,spirometry, and symptom burden using the modified Medical Research Council (mMRC) dyspneascale. Post‐bronchodilator forced expiratory volume in one second (FEV₁) and forced vitalcapacity (FVC) will be recorded in accordance with standard spirometric procedures.Participants will be followed at scheduled intervals throughout the six‐month treatmentperiod. Follow‐up assessments will include the occurrence and severity of COPDexacerbations, hospitalization, changes in post‐bronchodilator FEV₁, mMRC dyspnea score,treatment adherence, and adverse drug events. Medication adherence will be assessed usingstudy medication records and participant‐reported follow‐up information.The primary outcome will be the reduction in the frequency and severity of chronicobstructive 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 theStatistical Package for the Social Sciences (SPSS), version 27. Continuous variableswill be expressed as mean ± standard deviation (SD) or median with interquartilerange (IQR), as appropriate. Categorical variables will be presented as frequenciesand percentages.The independent‐samples t‐test will be used to compare normally distributed continuousvariables between the two treatment groups. The Mann‐Whitney U test will be used fornon‐normally distributed continuous variables. The chi‐square test or Fisher's exact testwill be used to compare categorical variables, as appropriate. A p‐value of ≤0.05 will beconsidered statistically significant.Where appropriate, stratified analyses will be conducted to assess the potentialinfluence of important baseline characteristics and confounding factors, including age,sex, smoking status, baseline forced expiratory volume in one second (FEV₁), baselineforced expiratory volume in one second/forced vital capacity (FEV₁/FVC) ratio, andcomorbidities.The study is expected to provide local evidence regarding the comparative effectiveness,tolerability, and safety of roflumilast and azithromycin as add‐on therapies inparticipants with severe chronic obstructive pulmonary disease (COPD)and frequentexacerbations. The findings may assist clinicians in selecting an appropriate additionalpharmacological treatment for participants who continue to experience exacerbationsdespite standard inhaled therapy.The Results section will present findings obtained after completion of the six‐monthfollow‐up period. Baseline demographic and clinical characteristics will be comparedbetween the roflumilast and azithromycin treatment groups to assess the comparability ofthe randomized groups.The primary outcome will be reported as the frequency and severity of Chronic ObstructivePulmonary Disease (COPD) exacerbations occurring during the six‐month follow‐up period.The number of exacerbations, the proportion of participants experiencing at least oneexacerbation, and exacerbation severity will be compared between the two treatmentgroups.Secondary outcomes will include changes in forced expiratory volume in one second (FEV₁),modified Medical Research Council (mMRC) dyspnea score, hospitalization rate, time tofirst chronic obstructive pulmonary disease (COPD) exacerbation, medication adherence,and adverse drug events.Spirometric outcomes will be presented using post‐bronchodilator forced expiratory volumein one second (FEV₁) and forced vital capacity (FVC). Changes from baseline to the end ofthe 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 whetherthey resulted in treatment discontinuation.Statistical analysis will be performed using the Statistical Package for the SocialSciences (SPSS), version 27. Continuous variables will be presented as mean ± standarddeviation (SD) or median with interquartile range (IQR), according to the distribution ofthe data. Categorical variables will be presented as frequencies and percentages.Appropriate statistical tests, including the independent‐samples t‐test, Mann‐Whitney Utest, chi‐square test, and Fisher's exact test, will be applied according to the type anddistribution of the data. A p‐value of ≤0.05 will be considered statisticallysignificant.The final results will determine whether roflumilast or azithromycin provides greaterbenefit in reducing chronic obstructive pulmonary disease (COPD )exacerbations andimproving clinical outcomes among patients with severe chronic obstructive pulmonarydisease (COPD) and frequent exacerbations receiving standard inhaled therapy.