Q&A: PERFORM Data Support Triple Therapy in Milder Uncontrolled Asthma

Explanatory phase 3 trials of single-inhaler triple therapy (SITT) in asthma have enrolled patients with moderate to severe disease, impaired lung function, and a history of exacerbations, leaving infrequently exacerbating patients outside the evidence base.¹ Even among patients adherent to medium- and high-dose ICS/LABA, 63.8% and 70.0%, respectively, remain uncontrolled, underscoring the unmet need in this population.¹ PERFORM was designed to close this gap using a pragmatic, open-label design reflecting routine clinical practice, without restricting patients by treatment history, smoking status, comorbidities, or exacerbation frequency.

PERFORM randomized 1236 adults with uncontrolled asthma 1:1 to once-daily FF/UMEC/VI via the ELLIPTA inhaler or non-ELLIPTA usual care ICS/LABA More than 80% of enrolled patients reported no severe exacerbation in the prior year.¹

At week 24, FF/UMEC/VI produced a significantly greater improvement in trough FEV1 versus usual care ICS/LABA (least squares mean difference, 68 mL [95% CI, 36-99]; P <.001).¹ Overall, 79.0% of patients achieved a clinically meaningful ACQ-7 response with FF/UMEC/VI versus 71.8% with usual care (odds ratio, 1.47 [95% CI, 1.13-1.92]; P =.004).¹ These results mark the first pragmatic randomized controlled trial evidence for FF/UMEC/VI in patients with uncontrolled, infrequently exacerbating asthma, a population historically excluded from SITT trials.¹

At the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain, John Oppenheimer, MD, clinical professor of medicine at Rutgers New Jersey Medical School and allergist at Pulmonary and Allergy Associates of New Jersey, presented a late-breaking abstract on PERFORM.2 Oppenheimer spoke with HCPLive ahead of the meeting about how the secondary endpoint data reshape thinking on triple therapy escalation.

Q&A: PERFORM Data Support Earlier Triple Therapy in Milder Uncontrolled Asthma

HCPLive: Why has this uncontrolled, infrequently exacerbating population been overlooked in prior SITT trials, and why does pragmatic RCT data here matter clinically?

Oppenheimer: We’ve generally examined new medicines by [conducting] a very rigid phase 3 trial, so we exclude people that may smoke or may have other comorbidities. We also exclude people that are not adherent [to treatments] because, obviously, this diminishes the efficacy of the study when you're trying to get FDA or EMA approval.

The analogy I draw is when I have somebody that tells me how many miles per gallon and how good a car is, it's done under ideal conditions. We drive it with somebody that's got their foot in the pedal, not escalating up and down. That's just consistent. I look at pragmatic trials as kicking the tire and letting it be in the real world, and it really shows if the signal can translate from a well-controlled trial to the real world, and that's exactly what this pragmatic study did.

HCPLive: How did the secondary endpoint findings presented at ERS change your interpretation of the PERFORM data?

Oppenheimer: It reinforces a lot of PERFORM data. What we've done in this particular study is we've looked at things like asthma control. If you think about many of the studies with regard to more severe asthmatics, the outcome we look at is exacerbation because that's an easy signal. It really is very palpable, and it's very expensive.

Only about 10% of patients with moderate disease with ongoing symptoms have [an] exacerbation once a year, and only 22% of those people having 1 exacerbation will go on to another exacerbation. Meaning that when we look at the exacerbation population, it is a real small minority of those patients with uncontrolled asthma.

What's really neat about PERFORM is we're looking at the average patient that really has moderate to severe asthma that needs to have their therapy escalated to gain control, and what PERFORM does is show that moving from dual therapy ICS/LABA to triple therapy ICS/LABA/LAMA translates to better outcomes [and] translates to better control.

HCPLive: Is PERFORM data sufficient to shift guideline conversations for milder uncontrolled disease?

Oppenheimer: Yes. What the study shows us is that many patients that are uncontrolled can do better if we step up therapy.

We need to be more aggressive early on in treating patients with triple therapy versus dual therapy, and if they do fail, then we would move to biologics if they're appropriate candidates.

HCPLive: How does heterogeneity in the usual care arm affect interpretation of the findings?

Oppenheimer: That's part of the problem. When you have a pragmatic study, it may not be as controlled as, say, a phase 3 trial, so heterogeneity will exist. But it just shows that a very diverse population still shows a signal of efficacy [with] triple versus dual.

Why might that be? You're already on dual therapy. What does adding the LAMA do? I don't know that we have a good answer, but there's interesting data that's translated from studies looking at small airways’ disease. What they do is they look at the ability for the inhaled therapy to result in less heterogeneity of the lung.

A study done by Tetsch-Kirschner in Advanced Therapeutics 2025 looks at visualized improvements of airway dysfunction comparing dual to triple therapy. People on dual therapy had areas of their lungs that weren't ventilating, and adding the LAMA resulted in a greater improvement in their ability to ventilate the peripheral airway compared to dual therapy.

Maybe we're getting the medicine to where the problem is, and we're opening up the lungs. It's exciting new data showing that adding this third arm on our controller therapy really translates to improve ventilation of the lung, improve symptoms, [and] improve lung function.

HCPLive: Do patients with this infrequently exacerbating phenotype notice lung function improvements day to day, or does symptom benefit stem from another mechanism?

Oppenheimer: It’s all over the page. There's real heterogeneity in lung function changes in patients’ perception of their shortness of breath. There were several studies done, one by Magdle in Chest almost 20 years ago, showing that a subgroup of people will perceive change in their lung function profoundly, while others may not.

The nice thing about PERFORM, by looking at the asthma control patient perception, [it] really speaks to the fact that they felt better on this therapy. You could see a difference in their feeling of control.

HCPLive: Did regional differences in asthma management affect generalizability of PERFORM findings for US allergists and pulmonologists?

Oppenheimer: The main thrust of controller therapy, whether we look at GINA or NHLBI, so ex-US versus US, is really very similar. It's controller therapy and escalation of the controller arm. I don't think it varies enough to make a big difference in the outcome.

HCPLive: Is there anything else about PERFORM you would like to highlight?

Oppenheimer: One of the things that I think is very exciting right now is the concept of remission in asthma. Remission is the nirvana of asthma. It is our goal. It's aspirational from the standpoint of doctors having to work harder than ever before, and it's inspirational because patients realize that they have the ability to have a level of control that nobody ever perceived before. What's exciting is PERFORM demonstrated that remission was more likely to occur with triple versus dual therapy.

References

1. Penz E, Noorduyn SG, Moore AC, et al. Effectiveness of FF/UMEC/VI versus ICS/LABA in patients with uncontrolled asthma treated in routine clinical practice (PERFORM): a pragmatic randomized controlled trial. J Asthma Allergy. 2026;19:599766. doi:10.2147/JAA.S599766

2. Oppenheimer J. The PERFORM Pragmatic RCT Comparing FF/UMEC/VI Versus ICS/LABA in Asthma. Late-breaker presented at the European Respiratory Society (ERS) Congress 2026 in Barcelona, Spain from September 5 – 9.