Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)

Johns Hopkins University1,032 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,032

Conditions

Chronic Obstructive Pulmonary Disease Severe Chronic Bronchitis

Interventions

RoflumilastDRUG

Prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 72 months

AzithromycinDRUG

Prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 72 months

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

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.

Locations (29)

Outcomes

Primary Outcomes

Time to first all-cause hospitalization or all-cause death

Composite time-to-event outcome defined as time from randomization to the first occurrence of all-cause hospitalization or all-cause death. Participants without an event will be censored at the date of last contact.

Time frame: Up to 72 months

Secondary Outcomes

Time to first moderate COPD exacerbation, all-cause hospitalization or all-cause death

Composite time-to-event outcome defined as time from randomization to the first occurrence of moderate COPD exacerbation, all-cause hospitalization, or all-cause death. Moderate COPD exacerbation is defined as treatment with antibiotics or systemic corticosteroids for a respiratory exacerbation not associated with hospitalization.

Time frame: Up to 72 months

Time to first of individual components of the primary and secondary composite outcomes

Time from randomization to the first occurrence of each individual component: moderate COPD exacerbation, all-cause hospitalization, and all-cause death. Each component will be evaluated separately.

Time frame: Up to 72 months

Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) scale

Change from baseline in physical function using the PROMIS physical function measure. Higher scores indicate better physical function. Score range 1-5 (i.e., a score of 5 is the most favorable and a score of 1 is least favorable).

Time frame: Baseline, 3 months, 6 months and every 6 months up to 72 months

Change in sleep disturbance as assessed by the PROMIS scale

Change from baseline in sleep disturbance using the PROMIS sleep disturbance measure. Higher scores indicate more sleep disturbance. Score range 1-5 (i.e., a score of 1 is least favorable and 5 is most favorable).

Data from ClinicalTrials.gov

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