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PARIS -- Triple therapy was effective and well-tolerated in symptomatic moderate-to-severe chronic obstructive pulmonary disease (COPD), even among GOLD B patients with a lower risk of exacerbations, results of the manufacturer-sponsored found.

Among over 3,000 patients, treatment with budesonide, glycopyrrolate, and formoterol in a metered-dose inhaler (MDI) yielded significant lung function improvements over the 24-week study compared with two of three dual therapies, as measured by FEV₁ area under the curve from 0-4 h (AUC_0-4), Gary Ferguson, MD, of the Research Institute of Southeast Michigan, reported.

There was a 104-mL least squares mean difference in FEV₁ AUC_0–4 compared with those on budesonide and formoterol fumarate (BFF) MDI and a 91-mL difference compared with open-label budesonide and formoterol fumarate (BUD/FORM) dry-powder inhaler (P<0.0001 for both).

And for change in pre-dose trough FEV₁, the triple therapy showed a 22-mL improvement compared with glycopyrrolate plus formoterol fumarate (GFF) MDI (P=0.0139).

Looking at moderate or severe exacerbations, model-estimated rates performed as part of a secondary analysis found that those on triple therapy had 0.46 exacerbations per year, which was lower than estimates for the dual therapies: 0.95 and 0.56 per year with the GFF and BFF MDIs, respectively, and 0.55 per year with BUD/FORM dry-powder inhaler.

"This makes you pause and ask the question ... 'Is a triple therapy only for people at very high risk or are some of these other things we're seeing here potentially a benefit in our patients?'" said Ferguson.

The results of the phase III trial were presented here at the European Respiratory Society meeting and published in the . Triple therapy in COPD means co-treatment with an inhaled steroid, long-acting muscarinic antagonist, and long-acting beta-agonist.

At week 24, those in the triple-therapy arm had a 116-mL improvement in FEV₁ AUC_0–4 versus patients in the BFF MDI arm (P<0.0001), and a non-significant 13-mL numerical advantage in trough FEV₁ over the GFF MDI.

"This concept that the triple is always going to win is going to be there in every single study, but the hardest piece of this is trying to figure out who the inclusion cohort should be," Charlie Strange, MD, of Medical University of South Carolina in Charleston, told MedPage Today. "To have a much-enlarged inclusion cohort that have a bunch of GOLD B patients that are more minimally symptomatic and still get the same kind of results on exacerbation frequency and lung function is rewarding."

Strange, who was not involved in the study, noted the unlikelihood of further large studies such as KRONOS and said that to move forward it would now be up to researchers to mine the available data sets.

"This is kind of the pinnacle of all of our past 15 years of studies where we're comparing single versus double versus triple therapies," he said. "What we really need is drug X to come through and then alter our treatment responses to all of these."

Ferguson told MedPage Today that he believes the results of KRONOS, but also TRIBUTE, IMPACT, and SUNSET could change how physicians are treating patients a year or two down the road, with triple therapy more in play even for moderate-to-severe COPD patients at lower risk of exacerbations, but said he hopes to see use of biomarkers to identify the most ideal patients.

"Clearly we got a better lung function signal and a better exacerbation signal in the subset of patients that had higher eosinophils counts in the KRONOS study," he said.

In a that accompanied the article, Mona Bafadhel, MRCP, of the University of Oxford in London, noted that participants had to be symptomatic and on two inhaled therapies for study inclusion before randomization to the different treatments.

"This study design meant that some patients had treatment withdrawn, and approximately 70% of the population in the screening phase were taking an inhaled corticosteroid," she explained. "Although it would seem that the population was of patients with symptomatic COPD without an exacerbation risk, it is conceivable that the majority of the population studied were responders to inhaled corticosteroids and that continuation of their inhaled corticosteroid treatment is beneficial to reducing their future risk of exacerbation."

Bafadhel called for a 12-month study to confirm the results.

The KRONOS study was a 24-week trial that randomized 3,097 patients in a 2:2:1:1 fashion. The triple therapy included the inhaled corticosteroid budesonide, the long-acting muscarinic antagonist glycopyrrolate, and the long-acting beta-agonist formoterol in a 320/18/9.6 μg MDI and was compared with three dual therapies: the GFF and BFF MDIs and the BUD/FORM dry-powder inhaler.

There were two primary endpoints: FEV₁ AUC_0-4 versus the dual therapies and change in pre-dose trough FEV₁ for triple therapy compared with dual therapies, both at 24 weeks. No exacerbation criteria were required of patients prior to study entry.

Common treatment-emergent adverse events were infections of the upper respiratory tract (6% to 10% with the triple therapy) and nasopharyngitis (7% to 9% depending on treatment). Incidence of pneumonia was similar across treatments. Two treatment-related deaths occurred in the GFF MDI arm.