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SAN DIEGO -- Patients with chronic obstructive pulmonary disease (COPD) without a high eosinophil burden and who were doing well on triple therapy had no increase in exacerbations when switched to the dual-bronchodilator therapy indacaterol/glycopyrronium (Ultibro Breezhaler) in the randomized, double blind, triple-dummy SUNSET trial reported here.

Patients in the study with consistent blood eosinophil counts of 300 μl or above, however, showed significant declines in lung function and increased risk for exacerbation on the fixed-dose dual therapy, suggesting that they are more likely to benefit from continued triple therapy.

The study is the first to evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to the once-daily long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) treatment in patients with moderate-to-severe COPD who do not have frequent exacerbations.

Findings from the study, funded by Breezhaler's manufacturer, Novartis, were reported this week at ATS 2018, the annual international meeting of the American Thoracic Society, and published simultaneously in the

Current GOLD (Global Initiative for Obstructive Lung Disease) recommendations call for the addition of inhaled corticosteroids (ICS) to LABA/LAMA as triple therapy in high-risk patients experiencing exacerbations on LABA/LAMA treatment alone. But the long-term use of ICS has been linked to numerous adverse events, including pneumonia, mycobacterial infection, diabetes onset and progression, and osteoporosis.

The aim of the study, led by Kenneth Chapman, PhD, of the University of Toronto, was to identify patients who might be able to safely step down treatment to a LABA/LAMA without ICS.

The showed that in patients with severe to very severe COPD susceptible to exacerbations, the risk of moderate or severe exacerbations was similar in patients who followed a stepwise ICS withdrawal compared with those who continued with ICS. No prior studies evaluating ICS withdrawal in patients on long-term triple therapy in the absence of frequent exacerbations, however, have been reported.

Asked for his perspective, James Donahue, MD, of the University of North Carolina School of Medicine at Chapel Hill, who was not involved with the study, called the SUNSET findings interesting, but said there is a great deal of confusion at the moment regarding the best treatment approach for severe COPD: "I'm sure physicians are getting more confused by the contrasting data from the triple therapy versus the LABA/LAMA studies and the studies withdrawing ICS from triple like WISDOM."

"The overall picture suggests to me that COPD patients with two exacerbations or one with a hospitalization -- GOLD D -- with a peripheral eosinophil count of >300 cells need to be on ICS plus bronchodilator. Probably I would use the triple therapy if patients meet one criteria, but stay tuned."

The 26-week, randomized, double-blind, triple-dummy SUNSET study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 μg once daily) or continuation of triple therapy (tiotropium 18 μg once daily plus combination of salmeterol/fluticasone propionate [50/500 μg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD.

The primary endpoint was non-inferiority on the change from baseline in forced expiratory volume in 1 second (FEV₁). Secondary endpoints were moderate or severe exacerbations, and patients with asthma were excluded from the trial to avoid ICS withdrawal in patients most likely to benefit from the treatment.

A total of 527 patients were randomized to receive indacaterol/glycopyrronium and 526 to have triple therapy.

Among the main study findings:

• ICS withdrawal led to a reduction in trough FEV₁ of −26mL (95% CI, −53 to 1 mL), with confidence limits exceeding the non-inferiority margin of −50 mL
• The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio 1.08; 95% CI, 0.83 to 1.40)
• Patients with ≥300 blood eosinophils/μL at baseline presented greater lung function loss and higher exacerbation risk

Adverse events were similar in the two groups.

Study limitations, Chapman et al noted, included the relatively short 6-month duration of the trial, "which may not be ideal for the evaluation of treatment effects on exacerbations due to seasonal variations."

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