Comparative Effectiveness of Roflumilast and Azithromycin in Reducing Exacerbations in Severe Chronic Obstructive Pulmonary Disease ( COPD ) Patients With Chronic Bronchitis Phenotype (COPD)
Study Overview
Status
Intervention / Treatment
Detailed Description
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.
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Adults aged ≥40 years.
- Confirmed diagnosis of COPD according to GOLD criteria.
- Post-bronchodilator FEV₁/FVC <0.70 on spirometry.
- Severe airflow limitation (FEV₁ <50% predicted).
- History of frequent exacerbations, defined as ≥2 moderate exacerbations or ≥1 severe exacerbation requiring hospitalisation during the previous 12 months.
- Receiving optimised inhaled therapy with LABA + LAMA, with or without ICS, according to clinical indication.
- Clinically stable at the time of enrolment, with no acute COPD exacerbation.
- Able to provide written informed consent and comply with study visits and treatment.
Exclusion Criteria:
- Diagnosis of bronchial asthma or other significant chronic respiratory disease.
- Active respiratory infection, pneumonia, tuberculosis, or current acute COPD exacerbation.
- Significant uncontrolled cardiovascular disease or clinically important cardiac arrhythmia.
- Severe hepatic impairment or significant liver disease.
- Known allergy or contraindication to roflumilast or azithromycin/macrolides.
- History of significant QT prolongation or use of medicines with a major risk of QT prolongation.
- Current or recent long-term treatment with roflumilast or prophylactic azithromycin/macrolide therapy.
- Patients requiring systemic corticosteroids or antibiotics for an acute exacerbation at the time of enrolment.
- Pregnant or breastfeeding women.
- Patients with conditions likely to interfere with study treatment, follow-up, or outcome assessment.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Group A : roflumilast
Group A will receive oral roflumilast 500 microgram once daily
|
out of total 70 patients , 35 patients will receive roflumilast 500 microgram once daily
|
|
Active Comparator: Group B : Azithromycin
Group B will receive oral azithromycin 250 mg once daily
|
out of 70 patients 35 patients will receive azithromycin 250mg once daily
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Number of moderate/severe chronic obstructive pulmonary disease (COPD) exacerbations over 6 months
Time Frame: 6 months
|
Reduction in frequency of chronic obstructive pulmonary disease (COPD) exacerbations over 6 months, assessed by the number of moderate/severe exacerbations .
|
6 months
|
|
Proportion of participants requiring hospitalization for COPD exacerbation over 6 months
Time Frame: 6 months
|
"Percentage of participants who experience a COPD exacerbation requiring hospital admission during the 6-month treatment period.
Hospitalization will be considered COPD-related when the participant is admitted to hospital due to an acute worsening of COPD symptoms requiring inpatient management."
|
6 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Changes in Lung Function
Time Frame: 6 months
|
Changes in forced expiratory volume in one second to first COPD exacerbation over 6 months
|
6 months
|
|
Hospital admission rate
Time Frame: 6 months
|
In this outcome measure frequency of hospital admission will be measured
|
6 months
|
|
Number of participants experiencing treatment-emergent adverse events
Time Frame: 6 months
|
The number and proportion of participants experiencing adverse events related to study treatment during the six-month treatment period will be recorded and compared between the roflumilast and azithromycin groups.
|
6 months
|
Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
General Publications
- Candela M, Costorella R, Stassaldi A, Maestrini V, Curradi G. Treatment of COPD: the simplicity is a resolved complexity. Multidiscip Respir Med. 2019 Jun 3;14:18. doi: 10.1186/s40248-019-0181-8. eCollection 2019. No abstract available.
- Asim, Z., Sadaf, A. and Shah, S.K.H., 2025. Breathing Easier? The True Efficacy of Roflumilast in COPD Compared to Placebo. Health Aff., 13(4): 2539-2564.
- Al-Jahdali H, Al-Lehebi R, Lababidi H, Alhejaili FF, Habis Y, Alsowayan WA, Idrees MM, Zeitouni MO, Alshimemeri A, Al Ghobain M, Alaraj A, Alhamad EH. The Saudi Thoracic Society Evidence-based guidelines for the diagnosis and management of chronic obstructive pulmonary disease. Ann Thorac Med. 2025 Jan-Mar;20(1):1-35. doi: 10.4103/atm.atm_155_24. Epub 2024 Sep 24.
- Ahmadian S, Sin DD, Lynd L, Harrison M, Sadatsafavi M. Benefit-harm analysis of azithromycin for the prevention of acute exacerbations of chronic obstructive pulmonary disease. Thorax. 2022 Nov;77(11):1079-1087. doi: 10.1136/thoraxjnl-2021-217962. Epub 2021 Nov 26.
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- SZMC-MPE-2026-003-009-005-0002
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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