A multi-center, randomized, 72-month, parallel- group, non-inferiority, phase III study to compare the effectiveness of roflumilast (Daliresp, 500 mcg quaque die (QD) or alternate regimen) therapy versus azithromycin (250 mg QD, 500 mg QD three times per week, or alternate regimen) to prevent hospitalization or death in a patients at high risk for COPD exacerbations.

RELIANCE is a U.S.-based pragmatic clinical trial funded by the Patient-Centered Outcomes Research Institute (PCORI) to compare long-term use of roflumilast vs. azithromycin in up to 1,250 patients. It is intended to support hospital efforts to reduce the risk of all-cause hospitalization and reduce pre-mature deaths in individuals with chronic obstructive pulmonary disease (COPD) who have been hospitalized in the prior year for a COPD exacerbation. The COPD Patient Powered Research Network (PPRN) and affiliated investigators will conduct the trial in sites in the U.S.

Both roflumilast and azithromycin have been shown to reduce the risk of COPD exacerbations compared to placebo. However, there has not been a head-to-head comparison of the two medications so the relative harms and benefits of the two medications are unknown. Eligible patients will be randomized (1:1) to receive either a prescription for roflumilast or a prescription for azithromycin, and will be followed for at least 6 and up to 72 months. Patients will be enrolled at participating clinical sites and follow up data will be collected via an online patient portal or via a call center. Baseline and outcome data will also be collected from site medical records.

Pragmatic, non-inferiority trial using an intention-to-treat analysis to evaluate whether daily azithromycin is non-inferior to daily roflumilast in patients at high risk of COPD exacerbations. The investigators will randomize individual patients to receive prescriptions for roflumilast or azithromycin (1:1 ratio), stratified by site and current smoking status (yes/no).

Inclusion Criteria:

1. Patient and treating clinician considering treatment intensification with roflumilast or azithromycin to reduce the risk of COPD exacerbations
2. Age ≥ 40 years
3. Current or past smoker of at least 10 pack-years
4. Diagnosis by treating clinician of severe COPD and associated chronic bronchitis
5. Hospitalized with a diagnosis of COPD exacerbation or respiratory complications due to Coronavirus Disease 2019 (COVID 19) in the past 12 months
6. Current medications include inhaled Long Acting Muscarinic Antagonist (LAMA), Long-Acting Beta-Agonist (LABA) /LAMA, or Inhaled Corticosteroids (ICS) /LABA(note patients prescribed or using Short-Acting Beta-Agonist (SABA), Short-Acting Muscarinic Antagonist (SAMA), or SABA/SAMA on a scheduled basis (e.g., every 6 hours) are eligible since the patient is receiving functional controller therapy)
7. English or Spanish speaking
8. Willing and able to provide a contact telephone number

Exclusion Criteria:

1. Unable or declines to provide informed consent
2. Declines to provide social security number, health insurance claims number or Tax Payer ID (as applicable)
3. History of intolerance to azithromycin or roflumilast that the patient or patient's treating clinician considers sufficiently serious to avoid either treatment option
4. Current treatment with long-term (more than 30 days) roflumilast, azithromycin or ensifentrine (previous treatment with 1 or more doses of azithromycin, roflumilast or ensifentrine is not an exclusion criterion, as long as the patient and clinician are seeking treatment intensification options and would be willing to use azithromycin or roflumilast, as per randomized treatment assignment.)
5. Known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic
6. History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin
7. Moderate to severe liver impairment (Child-Pugh B or C)
8. Current pregnancy
9. Any other clinician-determined exclusion as per the clinician's clinical practice
10. The clinicians will be provided the FDA-approved prescribing information for roflumilast and azithromycin. The prescribing information includes a list of warnings and precautions that identifies the potential for adverse effects and is intended to support clinical decision-making that takes into account the risks and benefits of roflumilast and azithromycin for each patient.

The Inter-University Consortium for Political and Social Research (ICPSR) at the University of Michigan will provide data archiving and dissemination services for RELIANCE. After entering into a Restricted-Use Data Contributor Agreement with ICPSR, the RELIANCE Data Coordinating Center (DCC) will prepare and transfer restricted-use files for the analyzable data set and supporting document to ICPSR. The data files will be prepared per Safe Harbor methods for compliance with the HIPAA Privacy Rule. IPD includes: demographic data, BMI, type of insurance, smoking history, COPD treatments; lung function measurements, comorbidities, use of study assigned treatment, responses to quality of life questions, adverse events, symptoms and information on hospitalizations and death.

The start date will be after 5/1/2027. Data and document transfer and curation is scheduled to be completed by 5/1/2027 after which PCORI (study funder) will determine the start date based on the publication status of the primary results manuscript or Final Research Report. There is no end date.

Investigators submit requests via ICPSR web-based data access request system. Requests include investigator, research staff and institution information, proposed research purpose/description, specific files needed, signed confidentiality pledges, data security plan, IRB approval or exemption for proposed research, assurance that data use is to develop/contribute to generalizable knowledge, and justification research project can be achieved using the requested data. Requests are evaluated by an independent committee. If approved, ICSPR and Investigator enter into a Restricted Data Use Agreement for Restricted Data in the Virtual Data Enclave (VDE), which describes investigator, research staff and institution obligations including data use only for described project, compliance with data security plan, access limited to persons identified in agreement, and no attempts to identify private persons are permitted. Data is made available via the VDE, a secure remote-access workspace.

Treatment assignments will be concealed prior to randomization. Once a patient is assigned to receive a treatment, the clinician, Site Coordinator and patient will not be masked. i.e., will know the treatment assignment