Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)

Study Overview
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Brief Summary
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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.

Detailed Description
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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 1,200 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. The primary endpoint is the combined outcome of all-cause hospitalization or death; the secondary endpoints include premature treatment discontinuation, patient-reported adverse effects, and physical, social, and emotional health. 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 and administrative/claims databases. 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).

Official Title
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Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)

Conditions
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Chronic Obstructive Pulmonary Disease Severe, Chronic Bronchitis

Intervention / Treatment
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* Drug: Roflumilast
* Drug: Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient and treating clinician considering treatment intensification with roflumilast or azithromycin to reduce the risk of COPD exacerbations Age ≥ 40 years Current or past smoker of at least 10 pack-years Diagnosis of severe COPD and associated chronic bronchitis Hospitalized with a diagnosis of COPD exacerbation or respiratory complications due to Covid 19 in the past 12 months Current medications include inhaled Long Acting Muscarinic Antagonist (LAMA), Long Acting Beta Agonist (LABA) /LAMA, or Inhaled Corticosteroids (ICS) /LABA English or Spanish speaking Exclusion Criteria: Unable or declines to provide informed consent; Declines to provide social security number or health insurance claims number (as applicable) History of intolerance to azithromycin or roflumilast that the patient or patient's treating clinician considers sufficiently serious to avoid either treatment option; Current treatment with long-term (more than 30 days) roflumilast or azithromycin (previous treatment with 1 or more doses of azithromycin or roflumilast 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.) Known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic; History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin Moderate to severe liver impairment (Child-Pugh B or C) Current pregnancy Any other clinician-determined exclusion as per the clinician's clinical practice

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The trial is a parallel, pragmatic non-inferiority trial with two treatment groups, roflumilast and azithromycin. Up to 1,200 participants will be randomized (1:1) to receive a prescription for one of the two treatments. Treatment assignments will be stratified by site and smoking status (former versus current) using a permuted block design with multiple block sizes.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Roflumilast arm<br>Participants will receive prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 72 months | Drug: Roflumilast<br>* Prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 72 months<br>* Other names: Daliresp;|
| Active Comparator: Azithromycin arm<br>Participants will receive prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 72 months | Drug: Azithromycin<br>* Prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 72 months<br>* Other names: Zithromax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of All-cause hospitalizations | All-cause hospitalizations | Up to 72 months | 
| Number of All-cause deaths | All-cause deaths | Up to 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of All-cause individual events | All-cause individual events | Up to 72 months | 
| Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) scale | Based on the scoring scale; a score of 5 is the most favorable and a score of 1 is least favorable. | Baseline, 3 months, 6 months and every 6 months up to 72 months | 
| Change in problems with sleep as assessed by the PROMIS scale | 1 is least favorable and 5 is most favorable | Baseline, 3 months, 6 months and every 6 months up to 72 months | 
| Change in fatigue as assessed by the PROMIS scale | 0 is most favorable and 4 and least favorable | Baseline, 3 months, 6 months and every 6 months up to 72 months | 
| Change in anxiety as assessed by the PROMIS scale | Score of 1 is most favorable and 5 is least favorable | Baseline, 3 months, 6 months and every 6 months up to 36 months | 
| Change in depression as assessed by the PROMIS scale | 1 is most favorable and 5 is least favorable | Baseline, 3 months, 6 months and every 6 months up to 72 months | 
| Number of Adverse Events | Adverse events | Up to 72 months | 
| Medication Adherence as assessed by patient self-report | Medication Adherence will be assessed by self-report via Call Center or Patient Portal; Medicare claims data in a subset. | Up to 72 months | 
| Number of participants that switch to alternate study medication | Patient will be assigned either azithromycin or roflumilast at randomization. We will assess any switch to either roflumilast from azithromycin or azithromycin from roflumilast by self-report via Call Center or Patient Portal, query of clinic staff; Medicare claims data in a subset | Up to 72 months | 
| Out of pocket cost for study medication | Out of pocket costs for roflumilast of azithromycin by self-report via Call Center or Patient Portal | Up to 72 months | 
| Change in weight | Weight in lbs | 3 and 6 months | 
| Number of participants that discontinued medication | This will be collected by self-report via Call Center or Patient Portal; query of clinic staff; Medicare claims data in a subset | Up to 72 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, COPD, Roflumilast, Daliresp, Azithromycin