Clinical trial NCT04069312: Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
Official title: Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease Severe
Chronic Bronchitis
Keywords: Chronic Obstructive Pulmonary Disease
Chronic Bronchitis
COPD
Roflumilast
Daliresp
Azithromycin
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
name: University of Illinois at Chicago
First posted: 2019-08-28
Enrollment: 1250
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: OTHER

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. 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).

Eligibility criteria: 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

Primary outcomes:
measure: Number of All-cause hospitalizations
timeFrame: Up to 72 months
measure: Number of All-cause deaths
timeFrame: Up to 72 months
Secondary outcomes:
measure: Number of All-cause individual events
timeFrame: Up to 72 months
measure: Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) scale
timeFrame: Baseline, 3 months, 6 months and every 6 months up to 72 months
measure: Change in problems with sleep as assessed by the PROMIS scale
timeFrame: Baseline, 3 months, 6 months and every 6 months up to 72 months
measure: Change in fatigue as assessed by the PROMIS scale
timeFrame: Baseline, 3 months, 6 months and every 6 months up to 72 months
measure: Change in anxiety as assessed by the PROMIS scale
timeFrame: Baseline, 3 months, 6 months and every 6 months up to 36 months
measure: Change in depression as assessed by the PROMIS scale
timeFrame: Baseline, 3 months, 6 months and every 6 months up to 72 months
measure: Number of Adverse Events
timeFrame: Up to 72 months
measure: Medication Adherence as assessed by patient self-report
timeFrame: Up to 72 months
measure: Number of participants that switch to alternate study medication
timeFrame: Up to 72 months
measure: Out of pocket cost for study medication
timeFrame: Up to 72 months
measure: Change in weight
timeFrame: 3 and 6 months
measure: Number of participants that discontinued medication
timeFrame: Up to 72 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Sacramento
country: United States
facility: University of California, Davis Health
state: California
city: Chicago
country: United States
facility: Northwestern
state: Illinois
city: Chicago
country: United States
facility: University of Illinois, Chicago
state: Illinois
city: Glenview
country: United States
facility: NorthShore Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Springfield
country: United States
facility: Baystate Health
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Kansas City
country: United States
facility: University of Missouri, Kansas City
state: Missouri
city: New York
country: United States
facility: Mount Sinai
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital/Northwell Health
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, School of Medicine
state: North Carolina
city: Durham
country: United States
facility: Duke
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente
state: Oregon
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburg Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Scott & White (BSW) Health-North
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Spokane
country: United States
facility: Providence Health and Services
state: Washington
Study officials:
affiliation: University of Illinois Chicago
name: Jerry Krishnan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins School of Medicine
name: Robert Wise, MD
role: PRINCIPAL_INVESTIGATOR
References: