Interpreting a Missed Primary End Point in COPD: Jorgen Vestbo, MD

The COPERNICOS (NCT04481555) trial, a multicenter, randomized, double-blind trial testing low-dose azithromycin (250 mg three times weekly) against placebo for preventing exacerbations in patients with severe chronic obstructive pulmonary disease (COPD), was presented at the European Respiratory Society (ERS) 2026 International Congress in Barcelona, Spain.

The trial's primary outcome, hospitalization-requiring exacerbations or death within 365 days, was not met, though several secondary outcomes favored azithromycin. Jorgen Vestbo, MD, is a professor of respiratory medicine at the University of Manchester and a past president of the ERS and co-author on the COPERNICOS trial.¹

In an interview with The American Journal of Managed Care^® (AJMC^®), Vestbo spoke about how to interpret those mixed results, the long-term antibiotic use tradeoffs in COPD, and where COPD treatment is headed.

This transcript was lightly edited for clarity.

AJMC: The primary outcome wasn't met, but several secondary outcomes looked favorable. How should clinicians and patients interpret a result like that?

Vestbo: I think the study was slightly underpowered, first because it was an investigator-led trial, so we had to pay for it ourselves, and secondly, it was during COVID-19, so there were fewer exacerbations than you would have anticipated, and I think it's difficult to interpret stuff like this. I think what helps is that there is the evidence base for the higher dose, the 500-milligram dose 3 times per week, and the reason we did it with 250 milligrams three times a week is that that's the dose clinicians usually choose, because the higher dose gives more side effects.

What we wanted to make sure of was that when we then reduce the dose, do we actually maintain the efficacy of the treatment? And you can argue, well, we didn't meet the primary endpoint, but everything pointed in that direction, and actually the point estimates for the reductions were of a similar size to those in the 500-milligram trial. We end up not saying that the 250-milligram dose is as efficacious or can just be picked, but what we want to say is that in those who have side effects on 500 milligrams 3 times weekly, it seems to be reasonable to shift them to 250 milligrams 3 times weekly, because it is difficult with all these almost-significant findings.

AJMC: Long-term antibiotic use is always a balancing act. How do you weigh the benefits seen here against broader concerns about antibiotic use in COPD care?

Vestbo: I think that's a difficult one, too. When I work in Denmark, we're in a fairly safe haven where, for instance, pneumococcus is still penicillin-sensitive, so we're very cautious about not bringing in too much antimicrobial resistance, and we know we do that with the macrolides. We have to be cautious, and I think it's a little bit the same as with the inhaled corticosteroids: you have to pick the right patients, and both when I treat COPD patients and asthma patients, I think they need to be monitored.

If they come back after a winter season and say, “Well, maybe it was a little bit better, but I'm not quite sure,” I would take them off the macrolides again, because usually, if they have an effect, they all come and say, “Well, I caught this cold, and I thought now it was going to my chest, and it just didn't.” And that's the effect of the macrolide. If they don't give me that story, I'm keen to take them off again.

And then in Denmark, we have a tradition that we usually take them off in June, July, and August, because the risk of having a respiratory tract infection is so much lower, so that's another way of doing it, and then they can rebuild their usual flora in their tract. Yeah.

AJMC: Between this trial and COPERNICOS, is there a bigger theme you're seeing in how COPD treatment is evolving?

Vestbo: I think also, with the biologics coming along, that we don't want to give patients the same treatment. It's not that they're all unique, because I think that would almost be too difficult with all these patients. I think there are a number of patients where breathlessness is the main issue. They don't have exacerbations, and they can be treated quite simply by finding the optimal bronchodilator treatment. But then for those who have exacerbations, we need to find out what it is that would work in this particular patient.

And also perhaps sometimes accepting that the inhaled corticosteroid won't work, and actually they didn't have an effect from the macrolide, so they won't get anything on top of the bronchodilator. I think that is equally important—that we don't just give them the drug anyway, just to feel safe. I think this is one way of guiding and actually also showing that if we don't think it is indicated, it's safe not to.

AJMC: As someone who's been deeply involved with ERS for years, including as a past president, what role do you think a congress like this plays in translating research like these two trials into real change for patients?

Vestbo: I'm a big fan of real congresses and not just virtual congresses, because they're good for networking, and by networking I don't mean just meeting your old friends, because you could do that anyway. I think for young researchers, that's how you start building networks. You walk around in poster sessions. You see somebody who has done something similar to your own field—not quite the same—and you start discussing, and suddenly you start building up a collaboration. I think that's extremely important.

References

1. Sivapalan P, Rønn C, Toennesen L, et al. Low-dose azithromycin for the prevention of exacerbations in severe chronic obstructive pulmonary disease (COPERNICOS trial). Presented at: European Respiratory Society (ERS) Congress 2026; September 5-9, 2026; Barcelona, Spain.