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Single Inhaler Triple Therapy Promising for Uncontrolled Asthma

MADRID — Triple therapy delivered in a single inhaler improved lung function and reduced exacerbations in patients with asthma poorly controlled with inhaled corticosteroid (ICS)-plus long-acting beta-agonist (LABA) treatment, a researcher reported here.

In the double-blind, parallel-group phase III trials TRIMARAN and TRIGGER, the addition of a long-acting muscarinic antagonist to inhaled ICS-LABA also showed benefit for improving asthma symptoms and control, reported Dave Singh, MD, of the University of Manchester in England, in a presentation at the European Respiratory Society (ERS) annual meeting. The research by Singh and colleagues was simultaneously published in the Lancet.

Pooled analysis of both studies showed that single inhaler triple therapy was associated with a 23% reduction in severe exacerbations, Singh stated.

In the TRIMARAN trial, which compared ICS/LABA/LAMA single inhaler therapy to medium doses of ICS plus LABA, triple therapy was associated with a 15% reduction in the rate of moderate to severe exacerbations (rate ratio 0.85, 95% CI 0.73-0.99, P=0.033).

In the TRIGGER study, in which the LAMA was added to high-dose ICS plus LABA therapy, the exacerbation rate was reduced by 12% (RR 0.88, 95% CI 0.75-1.03, P=0.11).

The two studies enrolled a combined 2,592 patients (61% female; 81% ages <65). Current smokers and former smokers with a ≥10 year smoking history were excluded from the trials, but other former smokers were not.

At ERS, Singh presented results of a prespecified analysis of patients enrolled in the two studies, designed to identify characteristics associated with better response to triple therapy.

The six characteristics used to classify patients were:

  • Gender
  • Age
  • BMI
  • Smoking status
  • Number of exacerbations over the previous year
  • Forced expiratory volume in 1 second (FEV1) reversibility

The analysis suggested that the effect of triple therapy was greater in males than females, in patients with lower BMIs, and in patients who had one or fewer exacerbations during the previous year. Younger age, higher FEV1 reversibility, and being a never-smoker were also associated with better responses.

Singh said the findings should be considered hypothesis generating, adding that the six characteristics “give us something to build on for further analysis.”

In addition to reducing exacerbations, the two trials showed that triple therapy improved lung function, as measured by FEV1.

Compared with ICS-LABA treatment alone, patients receiving the triple therapy were able to exhale significantly more air after 26 weeks of treatment in the TRIMARAN trial (57 mL, 95% CI 15-99, P=0.0080) and in the TRIGGER trial (73 mL, 95% CI 26-120, P=0.0025).

Four patients had treatment-related serious adverse events (one in TRIMARAN; three in TRIGGER), while three patients in TRIMARAN and two patients in TRIGGER had adverse events leading to death. None of the deaths were deemed to be related to treatment, the authors stated.

In an accompanying Lancet comment, J. Mark FitzGerald and Mohsen Sadatsafavi, both of the University of British Columbia in Vancouver, wrote that single-inhaler triple therapy should simplify the treatment of patients with uncontrolled asthma, and it may also prove to be an alternative to far more expensive biologic therapies for some patients.

“This therapy, as the authors alluded to, will be more cost-effective than biologics, although much less effective in terms of the reduction of exacerbations and no data are available to show a systemic steroid-sparing effect,” they wrote.

They further noted that it is not yet clear if a trial of triple therapy is warranted before putting patients on biologic treatments.

“Given the excellent predictor of response to the newer therapies such as the effect of anti-interleukin-5 therapies on peripheral eosinophil count and the frequency of previous exacerbations, and the substantial extrapulmonary benefits (in the presence of atopic dermatitis and nasal polyposis) that have been seen with dupilumab [Dupixent], an intermediate trial of (triple) therapy might not be appropriate for all patients,” they wrote.

FitzGerald and Sadatsafavi cited the lack of data on quality-of-life improvements as a study limitation.

“Given that the most impressive results of TRIMARAN and TRIGGER are associated with a reduction in exacerbations, which are essentially a future risk, it is especially important for the clinician when prescribing this therapy to explain the delayed effect to the patient,” they wrote.

The study was funded by Chiesi Farmaceutici. Some co-authors are company employees or employees of Chiesi USA.

Singh disclosed support from the National Institute for Health Research Manchester Biomedical Research Centre. Singh and co-authors disclosed multiple relevant relationships with industry including Chiesi Farmaceutici.

FitzGerald disclosed relevant relationships with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi Regeneron. Sadatsafavi disclosed no relevant relationships with industry.