Roflumilast vs Azithromycin for COPD Exacerbations

(RELIANCE Trial)

Not currently recruiting at 32 trial locations

Overseen By Umur Hatipoglu, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Johns Hopkins University

Must be taking: LAMA, LABA, ICS

Must not be taking: Macrolides, Ketolides

Disqualifiers: Liver impairment, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 3

Duration: 6 to 72 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores which treatment better prevents serious flare-ups in people with severe COPD (a lung disease) and chronic bronchitis. It compares two medications: roflumilast (an anti-inflammatory drug) and azithromycin (an antibiotic). Participants will receive one of these medications to determine if it reduces hospital visits or worse outcomes. Suitable candidates have severe COPD, recent hospital stays due to their condition, and are already using inhaled medications. As a Phase 4 trial, this research aims to understand how these FDA-approved treatments can benefit more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, it mentions that participants can continue using inhaled medications like LAMA, LABA, or ICS/LABA.

What is the safety track record for these treatments?

Research shows that safety information is available for both roflumilast and azithromycin, aiding in understanding how patients with COPD might tolerate them.

Studies have found that roflumilast can be taken daily. Common side effects include diarrhea, weight loss, nausea, headache, and back pain, observed in trials with over 4,400 patients. Roflumilast is approved to help reduce COPD flare-ups, indicating its safety for this use.

Azithromycin has been researched for its ability to prevent COPD flare-ups. Studies indicate it can reduce the risk of these flare-ups. While specific side effects are less emphasized in sources, azithromycin is a well-known antibiotic used for many infections, suggesting its safety is well understood.

Both treatments have undergone thorough research, providing a clearer picture of their safety for patients at high risk for COPD flare-ups. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for COPD exacerbations because they offer different approaches to managing the condition. Roflumilast is unique because it is a phosphodiesterase-4 (PDE4) inhibitor, which reduces inflammation in the airways, potentially leading to fewer flare-ups. This mechanism is different from standard treatments like inhaled corticosteroids or bronchodilators, which primarily focus on relaxing the muscles around the airways. On the other hand, Azithromycin is an antibiotic that also has anti-inflammatory properties, offering a dual-purpose approach by targeting possible infections and reducing inflammation. This combination of actions might offer a more comprehensive management of COPD exacerbations compared to existing treatments.

What evidence suggests that this trial's treatments could be effective for COPD exacerbations?

This trial will compare the effectiveness of Roflumilast and Azithromycin in reducing COPD exacerbations. Research has shown that Roflumilast can help reduce flare-ups in people with COPD. One study found that patients taking Roflumilast experienced 22.9% fewer moderate or severe flare-ups compared to those on a placebo. It also improves lung function and quality of life for those frequently experiencing these flare-ups.

Meanwhile, studies have demonstrated that Azithromycin effectively prevents COPD flare-ups. Long-term use of Azithromycin reduced flare-ups by 27% and improved quality of life. Another study found a 42% reduction in flare-ups when taken three times a week for a year. Both treatments have shown promising results in managing COPD symptoms and reducing hospital visits. Participants in this trial will receive either Roflumilast or Azithromycin to evaluate their effectiveness in managing COPD exacerbations. ^{1 2 6 7 8}

Who Is on the Research Team?

Jerry Krishnan, MD

Principal Investigator

University of Illinois Chicago

Robert Wise, MD

Principal Investigator

Johns Hopkins School of Medicine

Are You a Good Fit for This Trial?

This trial is for adults over 40 who have severe COPD with chronic bronchitis, are current or past smokers with a history of at least 10 pack-years, and were hospitalized for COPD exacerbations or respiratory issues from Covid-19 in the last year. They must be on certain inhaled medications and considering additional treatments to prevent further COPD flare-ups.

Inclusion Criteria

I was hospitalized for COPD flare-up or COVID-19 breathing issues in the last year.

My doctor and I are considering adding roflumilast or azithromycin to my treatment to prevent worsening of my COPD.

I am 40 years old or older.

Exclusion Criteria

I am currently on a long-term treatment with roflumilast or azithromycin.

I've had liver problems after taking azithromycin.

I have had a serious reaction to azithromycin or roflumilast.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either roflumilast or azithromycin for 6 to 72 months to prevent COPD exacerbations

6 to 72 months

Baseline, 3 months, 6 months and every 6 months up to 72 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Azithromycin
• Roflumilast

Trial Overview The RELIANCE study is testing whether roflumilast (Daliresp) can be as effective as azithromycin in preventing hospitalizations or death among high-risk COPD patients. Participants will randomly receive one of these drugs over a period of six years to compare their effectiveness.

How Is the Trial Designed?

Group I: Roflumilast arm Active Control 1 Intervention

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

Group II: Azithromycin arm Active Control 1 Intervention

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

Azithromycin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in United States as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Approved in Canada as Azithromycin for:

• Respiratory tract infections
• Skin and soft tissue infections
• Sexually transmitted diseases
• Toxoplasmosis
• Malaria
• Preterm prelabor rupture of membranes

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

University of Illinois at Chicago

Collaborator

Trials

653

Recruited

1,574,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Published Research Related to This Trial

In a real-life study of 55 severe COPD patients already on triple therapy, adding roflumilast significantly reduced the yearly rate of exacerbations from 3.57 to 2.75 (P = 0.022), especially benefiting those with a history of 4 or more exacerbations.

However, the treatment was associated with a high rate of side effects (69.1%), primarily gastrointestinal, leading to a 49.1% discontinuation rate, indicating that while effective, roflumilast may not be well-tolerated in many patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roflumilast added to triple therapy in patients with severe COPD: a real life study. Muñoz-Esquerre, M., Diez-Ferrer, M., Montón, C., et al.[2022]

In a study involving 101 patients with COPD, treatment with azithromycin (AZM) for three days showed similar clinical improvement compared to a longer 10-day treatment with acetyl cefuroxime (ACF), with a significant enhancement in expectoration symptoms.

Patients treated with AZM experienced fewer side effects (10%) compared to those on ACF (18%), suggesting that AZM may be a safer and effective alternative for managing COPD exacerbations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A randomized comparative study of 3 days of azithromycin treatment and 10 days of cefuroxime treatment in exacerbations in patients with chronic obstructive pulmonary disease]. Alvarez Gutiérrez, FJ., Soto Campos, G., del Castillo Otero, D., et al.[2015]

A single 2-g dose of azithromycin extended release (AZ-ER) resulted in a higher resolution of acute bacterial rhinosinusitis (ABRS) symptoms (32.6%) compared to 10 days of levofloxacin (LFX) (23.4%), indicating that AZ-ER may provide quicker symptom relief.

Both treatments had similar rates of treatment-related adverse events, but AZ-ER had a higher incidence (23.3%) compared to LFX (15.3%), with gastrointestinal issues being the most common side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Onset of symptom resolution in adults with acute bacterial rhinosinusitis treated with a single dose of azithromycin extended release compared with 10 days of levofloxacin: a retrospective analysis of a randomized, double-blind, double-dummy trial. Marple, BF., Roberts, CS., de Caprariis, PJ., et al.[2013]

Macrolides, like azithromycin, can help reduce the number of exacerbations in patients with chronic obstructive pulmonary disease (COPD) who frequently experience these episodes.

However, after more than one year of treatment, azithromycin does not maintain its effectiveness in reducing exacerbation frequencies, suggesting that its benefits may diminish over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Azithromycin Maintenance Treatment in Patients with Frequent Exacerbations of Chronic Obstructive Pulmonary Disease. Talman, S., Uzun, S., Djamin, RS., et al.[2021]

In a study of 3,875 COPD patients, roflumilast was associated with higher mortality rates (19%) compared to azithromycin (15%), indicating a potential safety concern for roflumilast.

Roflumilast also showed higher rates of COPD-related and all-cause hospitalizations compared to azithromycin, suggesting it may be less effective in preventing exacerbations in COPD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Roflumilast and Azithromycin for the Treatment of Chronic Obstructive Pulmonary Disease. Lam, J., Tonnu-Mihara, I., Kenyon, NJ., et al.[2022]

Roflumilast, a selective phosphodiesterase 4 inhibitor, significantly improved lung function (measured by FEV1) in patients with severe COPD compared to placebo, despite the increases being small.

In addition to improving lung function, roflumilast reduced the rate of COPD exacerbations by 17% over placebo, and it was well-tolerated, with a similar rate of serious adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roflumilast: in chronic obstructive pulmonary disease. Sanford, M.[2021]

Roflumilast is an effective treatment for patients with moderate to severe chronic obstructive pulmonary disease (COPD), improving lung function and reducing the risk of exacerbations, especially in those with chronic bronchitis.

While generally well tolerated, the most common side effect is diarrhea, and although there is a risk of psychiatric issues and weight loss, roflumilast does not increase the risk of respiratory infections and may lower cardiovascular risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Roflumilast: A Review in COPD. Garnock-Jones, KP.[2022]

Long-term low-dose azithromycin treatment in 92 COPD patients significantly reduced the number of exacerbations, particularly in those with frequent exacerbations and specific GOLD classifications (GOLD 1, 2, and C).

Azithromycin works by suppressing inflammation and enhancing immune responses, and its prophylactic use could save healthcare costs significantly, with an estimated savings of EUR 950 million in Belgium for COPD exacerbation treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azithromycin in the treatment of patients with exacerbation of chronic obstructive pulmonary disease. Płusa, T.[2020]

Roflumilast is an effective oral treatment for moderate to severe COPD, improving lung function and reducing exacerbation rates, especially when used alongside long-acting bronchodilators.

The treatment is generally well-tolerated, with mild to moderate side effects like nausea, diarrhea, and weight loss, which are mostly self-limiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. Diamant, Z., Spina, D.[2014]

Roflumilast, a phosphodiesterase-4 inhibitor, has shown potential as an effective anti-inflammatory treatment for asthma and COPD, based on various studies including animal and human trials.

The drug has a favorable safety profile with no documented drug interactions, making it a promising option for patients, although further research is necessary to confirm its role in therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential role of roflumilast: the new phosphodiesterase-4 inhibitor. Karish, SB., Gagnon, JM.[2022]

A single dose of 2.0 g azithromycin (ZSR) showed an 83.3% clinical cure rate for acute exacerbation of chronic obstructive pulmonary disease (AE-COPD), which is comparable to the 88.2% cure rate of intravenous therapy, indicating its efficacy as a treatment option.

Patients treated with ZSR had a significantly shorter hospital stay (average of 9.9 days) and lower medical costs compared to those receiving intravenous therapy (average of 12.5 days), suggesting that ZSR may be a more efficient and cost-effective treatment for AE-COPD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of single-dose 2.0 g azithromycin in the treatment of acute exacerbation of chronic obstructive pulmonary disease. Asai, N., Ohkuni, Y., Iwasaki, T., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2650599/

Use of azithromycin in the treatment of acute exacerbations ... This review summarizes the data on the use of the drug azithromycin for this particular patient population with a focus on 3-day and single-day therapy.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1104623

Azithromycin for Prevention of Exacerbations of COPD Azithromycin taken daily for 1 year, when added to usual treatment, decreased the frequency of exacerbations and improved quality of life but caused hearing ...

3. thorax.bmj.com thorax.bmj.com/content/early/2025/07/02/thorax-2025-223095

Identifying azithromycin responders with an individual ... Objective Long-term azithromycin treatment effectively prevents acute exacerbations of chronic obstructive pulmonary disease (COPD).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10406447/

Systemic and functional effects of continuous azithromycin ... The COLUMBUS trial also showed that 500 mg of azithromycin three times a week for 1 year significantly reduced (42%) the exacerbation rate ...

5. atsjournals.org atsjournals.org/doi/full/10.1513/AnnalsATS.202308-745ED

Cost-Effectiveness of Long-Term Azithromycin for Chronic ... Largely on the basis of the results of the MACRO trial, a large randomized controlled trial that found 27% reduction in exacerbations among patients with COPD ...

6. thorax.bmj.com thorax.bmj.com/content/77/11/1079

Benefit–harm analysis of azithromycin for the prevention of ... Conclusions Long-term therapy with azithromycin confers a net benefit to ex-smoker patients with COPD with a recent history of exacerbations and an even larger ...

7. atsjournals.org atsjournals.org/doi/10.1164/rccm.201901-0094OC

Azithromycin during Acute Chronic Obstructive Pulmonary ... Long-term treatment with 250 mg azithromycin once daily has proved to be effective in preventing AECOPDs by decreasing the exacerbation rate and ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10660475/

The Effectiveness and Safety of Long-Term Macrolide ... Azithromycin and erythromycin were identified as effective macrolides in averting COPD exacerbations, while there were insufficient data to ...