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Treatment with the first approved once-daily, single inhaler triple therapy for COPD resulted in a significantly lower rate of exacerbations, as well as better lung function and quality of life compared to dual therapy in patients with a history of exacerbations, researchers reported Wednesday.

Results from the huge IMPACT trial supported an extra benefit from the GlaxoSmithKline and Innoviva product Trelegy Ellipta -- containing an inhaled corticosteroid, a long-acting muscarinic antagonist (LAMA) and a long-acting β2-agonist (LABA) -- versus two of GlaxoSmithKline's two-drug inhalers.

The trial, reported Wednesday in the with GlaxoSmithKline researcher David Lipson, MD, as lead author, showed statistically significant and clinically relevant reductions in COPD exacerbations for the three-drug product.

Pulmonary disease specialist James Donohue, MD, of the University of North Carolina School of Medicine, Chapel Hill, said despite several limitations to the study, the robust difference in outcomes between the triple and dual therapy groups was impressive.

"The triple treatment was compared to two really good dual combination therapies and it beat both easily," he told MedPage Today. "That was something of a surprise."

Donahue, who was not involved with the study, noted that the findings challenge the common belief that treatment with an inhaled steroid adds little value to LAMA-LABA dual therapy.

"The idea is that the LAMA-LABA combination is so effective that patients don't need steroids, which have side effects," he said. "The new findings kind of turn things upside down."

At the same time, however, an editorial co-written by NEJM's editor-in-chief said the study's design called the results into question.

Trelegy Ellipta became the first single inhaler, dry powder treatment for COPD to combine a steroid (fluticasone furoate), LAMA (umeclidinium), and LABA (vilanterol) when it was approved by the FDA last September.

All patients recruited for the IMPACT trial had symptomatic COPD and a history of exacerbations occurring within a year of enrollment.

Triple therapy is recommended in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) treatment guidelines for patients with clinically significant symptoms despite treatment with an inhaled steroid and a LABA or LABA-LAMA combined treatment who have an elevated risk for exacerbations.

Lipson and colleagues noted that some controversy remains regarding the relative benefits of triple therapy compared to dual therapy in this patient population.

IMPACT compared treatment outcomes among patients treated for 52 weeks with Trelegy Ellipta with fluticasone furoate-vilanterol (Relvar/Breo Ellipta) and umeclidinium-vilanterol (Anoro Ellipta).

A total of 10,355 patients were recruited for the trial and the primary study outcome was annual rate of moderate or severe COPD exacerbations during treatment.

Among the main study findings:

• The rate of moderate to severe exacerbations in the triple-therapy group was 0.91 per year, compared with 1.07 per year in the fluticasone furoate-vilanterol group (RR 0.85, 95% CI 0.80 to 0.90) and 1.21 per year in the umeclidinium-vilanterol group (RR 0.75, 95% CI 0.70 to 0.81)
• The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, compared to 0.19 in the umeclidinium-vilanterol group (RR 0.66, 95% CI 0.56 to 0.78), though the three-drug product was not significantly superior to the fluticasone-vilanterol combination
• More cases of pneumonia occurred with inhaled steroid therapy, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with LAMA-LABA dual therapy

Adverse events led to discontinuation of treatment or withdrawal from the trial in 6% of the triple-therapy group, 8% in the fluticasone-LABA group, and 9% for the LAMA-LABA group.

In contrast to the widely reported , in which dual therapy with a LAMA-LABA was associated with better outcomes than dual therapy with an inhaled steroid and LABA, dual-therapy patients in the IMPACT trial fared better on the inhaled glucocorticoid-LABA therapy.

In an editorial, Samy Suissa, PhD, of McGill University, Montreal, and NEJM editor-in-chief Jeffrey M. Drazen, MD, wrote that the trial results are "challenging to interpret," because 40% of recruited patients were receiving triple therapy and 70% were being treated with an inhaled steroid at randomization.

"Thus, for the patients assigned to the LAMA-LABA group, many of whom were actually step-down in their treatment, inhaled glucocorticoid were abruptly withdrawn at the time of randomization; this could lead to COPD exacerbation," Suissa and Drazen wrote.

They added that the inclusion of patients with a history of asthma may have also contributed to a rapid increase in exacerbations in the first month after randomization to the LAMA-LABA group.

"During the subsequent 11 months of follow-up, the incidence of exacerbations with LAMA-LABA was practically identical to that with triple therapy," Suissa and Drazen wrote. "This (study design characteristic) probably also explains the lower incidence of exacerbations with LABA-inhaled glucocorticoid than with LAMA-LABA, a finding diametrically opposite to those of the FLAME trial."

The editorial writers noted that this aspect of the trial design also "probably resulted in falsely exaggerating the benefit of triple therapy in comparison to the LAMA-LABA comparator group."

They wrote that the inclusion of patients who were being treated with an inhaled steroid and who had asthma potentially inflated the effectiveness of triple therapy over dual bronchodilator therapy.

"As such, we think that the IMPACT trial falls short of providing the awaited robust evidence to better understand the potential for stepping up to single inhaler triple therapy in clinical practice."

"Until further evidence is available, we think that clinicians should rely on the updated GOLD 2017 guidelines recommending that escalation to triple therapy occur only after maximized bronchodilator-treatment with LAMA-LABA regimens and be limited to patients with more symptomatic GOLD group D COPD with frequent exacerbations," they concluded.