Chronic Bronchitis, Chronic Obstructive Pulmonary Disease Severe
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, COPD, Roflumilast, Daliresp, Azithromycin
Brief summary
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
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).
Interventions
DRUGRoflumilast
Prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 72 months
DRUGAzithromycin
Prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 72 months
Sponsors
Johns Hopkins University
Patient-Centered Outcomes Research Institute
University of Illinois at Chicago
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
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
Intervention model description
The trial is a parallel, pragmatic non-inferiority trial with two treatment groups, roflumilast and azithromycin. Up to 1,250 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.
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to first all-cause hospitalization or all-cause death | Baseline to study exit (up to 72 months) | Composite time-to-event outcome defined as time from randomization to the first occurrence of all-cause hospitalization or all-cause death. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to first moderate COPD exacerbation, all-cause hospitalization, or all-cause death | Baseline to study exit (up to 72 months) | 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 to first moderate COPD exacerbation | Baseline to study exit (up to 72 months) | Time from randomization to the first moderate COPD exacerbation. |
| Time to first all-cause hospitalization | Baseline to study exit (up to 72 months) | Time from randomization to the first all-cause hospitalization. |
| Time to all-cause death | Baseline to study exit (up to 72 months) | Time from randomization to all-cause death. |
| Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) scale | Measured at study registration, 3 months, and 6 months | Change in physical function from study registration to 6 months 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). |
| Change in sleep disturbance as assessed by the PROMIS scale | Measured at study registration 3 months, and 6 months | Change in sleep disturbance from study registration to 6 months using the PROMIS sleep disturbance measure. Lower scores indicate more sleep disturbance. Score range 1-5 (i.e., a score of 1 is most favorable and 5 is least favorable). |
| Change in fatigue as assessed by the PROMIS scale | Measured at study registration 3 months, and 6 months | Change in fatigue from study registration to 6 months using the PROMIS fatigue measure. Higher scores indicate greater fatigue. Score range 0-4 (i.e., a score of 0 is most favorable and 4 is least favorable). |
| Change in anxiety as assessed by the PROMIS scale | Measured at study registration, 3 months, and 6 months | Change in anxiety from study registration to 6 months using the PROMIS anxiety measure. Higher scores indicate greater anxiety. Score range 1-5 (i.e., a score of 1 is most favorable and 5 is least favorable). |
| Change in depression as assessed by the PROMIS scale | Measured at study registration, 3 months, and 6 months | Change in depression from study registration to 6 months using the PROMIS depression measure. Higher scores indicate greater depression. Score range 1-5 (i.e., a score of 1 is most favorable and 5 is least favorable). |
| Rate of Difficulty hearing or ringing in ears | 1 week until study exit (up to 72 months)] | Event rate (per person-year) reporting difficulty hearing or ringing in ears during follow-up |
| Rate of Diarrhea | 1 week until study exit (up to 72 months) | Event rate (per person-year) reporting diarrhea during follow-up |
| Rate of Nausea | 1 week until study exit (up to 72 months | Event rate (per person-year) reporting nausea during follow-up |
| Number of participants reporting thoughts of suicide or self-harm | 1 week until study exit (up to 72 months | Number of participants reporting suicidal ideation during follow-up |
| Macrolide-resistant organisms in sputum | Randomization to study exit (up to 72 months) | The number of participants with a positive sputum test for macrolide resistant organisms in the subset of participants whose electronic health record included testing while in the study |
| Proportion of participants reporting treatment adherence at 1 week | I week | Proportion of participants reporting use of assigned treatment at 1 week |
| Proportion of participants reporting treatment adherence at 3 months | 3 months | Proportion of participants reporting use of assigned study treatment at 3 months. |
| Proportion of Participants reporting Treatment adherence from 6 months to study exit (up to 72 months) | 6 months to study exit (up to 72 months) | For each participant, adherence is defined as the proportion of evaluable follow-up assessments at which the participant reports use of assigned study treatment. The outcome summarizes participant-reported adherence across follow-up from 6 months to study exit (up to 72 months) among participants with at least one evaluable medication use assessment as an event rate (per person year). |
| Number of participants who switch to alternate study treatment | 1 week, 3 months, 6 months and every 6 months up to 72 months | Number of participants with any follow-up report of prescription for the alternative study treatment after randomization. |
| Out of pocket cost for study treatment | 1 week, 3 months, 6 months and every 6 months up to 72 months | Participant-reported out-of-pocket cost (measured in U.S. dollars) for assigned study treatment. |
| Change in weight (pounds) | Measured at baseline, 3 months, and 6 months | Change from baseline in participant-reported weight (measured in pounds) |
| Number of participants who discontinued assigned study treatment | 1 week, 3 months, 6 months and every 6 months up to 72 months | Number of participants meeting protocol-defined treatment discontinuation, defined as the earliest follow-up assessment at which the participant reports not taking assigned study treatment during the interval since the prior assessment, with no subsequent report of treatment use. Because medication use is collected over recall intervals rather than exact stop dates, discontinuation reflects the earliest follow-up time point consistent with persistent non-use of assigned study treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJerry Krishnan, MD, PhD
University of Illinois at Chicago
PRINCIPAL_INVESTIGATORRobert Wise, MD
Johns Hopkins School of Medicine
Outcome results
None listed