Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04069312
• Collaborator: Patient-Centered Outcomes Research Institute (Other)
• Enrollment: 3,200
• Locations: 30
• Arms: 2
• Anticipated Duration (Months): 47.7
• Patients Per Site: 106.7
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

A multi-center, randomized, 36-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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease Severe; Chronic Bronchitis	Drug: Roflumilast; Drug: Azithromycin	Phase 3

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 3,200 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 36 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).

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 3200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: The trial is a parallel, pragmatic non-inferiority trial with two treatment groups, roflumilast and azithromycin. Up to 3,200 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.The trial is a parallel, pragmatic non-inferiority trial with two treatment groups, roflumilast and azithromycin. Up to 3,200 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)
• 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., they will know the treatment assignment
• Primary Purpose: Other
• Official Title: Roflumilast or Azithromycin to Prevent COPD Exacerbations (RELIANCE)
• Actual Study Start Date: Feb 11, 2020
• Anticipated Primary Completion Date: Feb 1, 2024
• Anticipated Study Completion Date: Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Roflumilast arm Participants will receive prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 36 months	Drug: Roflumilast; Prescription for Roflumilast (250 mcg/day x 4 weeks, then 500 mcg/day or alternate regimen) x 6 to 36 months; Other Names: Daliresp
Active Comparator: Azithromycin arm Participants will receive prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 36 months	Drug: Azithromycin; Prescription for Azithromycin (250 mg/day, or 500 mg three times per week, or alternate regimen) x 6 to 36 months; Other Names: Zithromax

Outcome Measures

Primary Outcome Measures

1. Number of All-cause hospitalizations [Up to 36 months]

   All-cause hospitalizations

2. Number of All-cause deaths [Up to 36 months]

   All-cause deaths

Secondary Outcome Measures

1. Number of All-cause individual events [Up to 36 months]

   All-cause individual events

2. Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS) scale [Baseline, 3 months, 6 months and every 6 months up to 36 months]

   Based on the scoring scale; a score of 5 is the most favorable and a score of 1 is least favorable.

3. Change in problems with sleep as assessed by the PROMIS scale [Baseline, 3 months, 6 months and every 6 months up to 36 months]

   1 is least favorable and 5 is most favorable

4. Change in fatigue as assessed by the PROMIS scale [Baseline, 3 months, 6 months and every 6 months up to 36 months]

   0 is most favorable and 4 and least favorable

5. Change in anxiety as assessed by the PROMIS scale [Baseline, 3 months, 6 months and every 6 months up to 36 months]

   Score of 1 is most favorable and 5 is least favorable

6. Change in depression as assessed by the PROMIS scale [Baseline, 3 months, 6 months and every 6 months up to 36 months]

   1 is most favorable and 5 is least favorable

7. Number of Adverse Events [Up to 36 months]

   Adverse events

8. Medication Adherence as assessed by patient self-report [Up to 36 months]

   Medication Adherence will be assessed by self-report via Call Center or Patient Portal; Medicare claims data in a subset.

9. Number of participants that switch to alternate study medication [Up to 36 months]

   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

10. Out of pocket cost for study medication [Up to 36 months]

    Out of pocket costs for roflumilast of azithromycin by self-report via Call Center or Patient Portal

11. Change in weight [3 and 6 months]

    Weight in lbs

12. Number of participants that discontinued medication [Up to 36 months]

    This will be collected by self-report via Call Center or Patient Portal; query of clinic staff; Medicare claims data in a subset

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233
2	University of Arizona	Tucson	Arizona	United States	85724
3	University of California, Davis Health	Sacramento	California	United States	95817
4	Denver Health	Denver	Colorado	United States	80204
5	Northwestern	Chicago	Illinois	United States	60611
6	University of Illinois, Chicago	Chicago	Illinois	United States	60612
7	NorthShore Hospital	Glenview	Illinois	United States	60026
8	University of Iowa	Iowa City	Iowa	United States	52242
9	Ochsner Medical Center	New Orleans	Louisiana	United States	70121
10	Johns Hopkins University	Baltimore	Maryland	United States	21287
11	Baystate Health	Springfield	Massachusetts	United States	01199
12	University of Michigan	Ann Arbor	Michigan	United States	48109
13	Henry Ford Health System	Detroit	Michigan	United States	48202
14	University of Missouri, Kansas City	Kansas City	Missouri	United States	64108
15	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
16	Mount Sinai	New York	New York	United States	10029
17	Lenox Hill Hospital/Northwell Health	New York	New York	United States	10075
18	University of North Carolina, School of Medicine	Chapel Hill	North Carolina	United States	27599
19	Duke	Durham	North Carolina	United States	27705
20	Case Western Reserve University	Cleveland	Ohio	United States	44113
21	Cleveland Clinic	Cleveland	Ohio	United States	44195
22	Ohio State University	Columbus	Ohio	United States	43210
23	Kaiser Permanente	Portland	Oregon	United States	97227
24	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
25	University of Pittsburg Medical Center	Pittsburgh	Pennsylvania	United States	15213
26	Medical University of South Carolina	Charleston	South Carolina	United States	29425
27	Baylor Scott & White (BSW) Health-North	Dallas	Texas	United States	75246
28	University of Vermont	Burlington	Vermont	United States	05401
29	Providence Health and Services	Spokane	Washington	United States	99204
30	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Johns Hopkins University
• Patient-Centered Outcomes Research Institute

Investigators

• Principal Investigator: Jerry Krishnan, MD, PhD, University of Illinois, Chicago
• Principal Investigator: Robert Wise, MD, Johns Hopkins School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT04069312
• Other Study ID Numbers: IRB00179281
• First Posted: Aug 28, 2019
• Last Update Posted: Mar 28, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Johns Hopkins University: Chronic Obstructive Pulmonary Disease; Chronic Bronchitis; COPD; Roflumilast; Daliresp; Azithromycin
• Additional relevant MeSH terms: Bronchitis; Bronchitis, Chronic; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Azithromycin

Study Results

No Results Posted as of Mar 28, 2022