One Inhaler Effective for Asthma Triple Therapy

Ingrid Hein

October 01, 2019

MADRID — For patients whose asthma is not well controlled, the addition of a long-acting muscarinic antagonist to the two-drug combination of an inhaled corticosteroid and a long-acting beta2 agonist in a single inhaler improves lung function and reduces asthma exacerbations, according to new research.

"This will have an impact on patients. For the first time, we've shown that triple therapy is effective with one inhaler," said investigator Johann Christian Virchow, MD, from Rostock Medical University in Germany.

"We know that even when you use the two-drug combination in high doses, we have patients whose asthma remains uncontrolled," he told Medscape Medical News. The third therapy offers a reduction in exacerbations, "especially for those with bronchoconstriction."

Virchow presented results from the triple-therapy study, also published online in the Lancet, here at the European Respiratory Society 2019 International Congress.

He and his colleagues evaluated the first two double-blind randomized phase 3 studies to compare triple therapy with a two-drug combination for asthma: the Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA (TRIMARAN) trial (NCT02676076) and the Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium (TRIGGER) trial (NCT02676089).

For the first time, we've shown that triple therapy is effective with one inhaler.

Of the 2592 participants in the two studies, 1579 (61%) were female and 514 (20%) had experienced more than one exacerbation in the previous year. All were18 to 75 years of age, had an asthma diagnosis for at least 1 year before the age of 40, had a prebronchodilator forced expiratory volume in 1 second (FEV₁) below 80%, had an Asthma Control Questionnaire score of at least 1.5, and had at least one exacerbation in the previous year.

In TRIMARAN, patients were randomly assigned to two inhalations twice daily from a single inhaler, for 52 weeks, of beclometasone dipropionate 100 μg plus formoterol fumarate 6 μg with or without the long-acting muscarinic antagonist glycopyrronium 10 μg.

In TRIGGER, patients were randomly assigned to two inhalations twice daily, for 52 weeks, of beclometasone 200 μg plus formoterol 6 μg plus glycopyrronium 10 μg in a single inhaler or to open-label beclometasone 200 μg plus formoterol 6 μg in a single inhaler plus two inhalations once daily of the long-acting muscarinic antagonist tiotropium 2.5 μg from another inhaler.

Improvements in lung function with single-inhaler triple therapy were seen at week 26 in both studies.

In TRIMARAN, predose FEV₁ was 57 mL higher with single-inhaler triple therapy than with the two-drug combination (P = .0080), and there was a 15% reduction in the rate of moderate and severe exacerbations (P = .033).

In TRIGGER, predose FEV₁ was 73 mL higher with single-inhaler triple therapy than with the two-drug combination plus tiotropium (P = .0025), and there was a 15% reduction in the rate of moderate and severe exacerbations (P = .11).

"Those with severe exacerbations got the most benefit," Virchow reported.

These reductions in the exacerbation rate are comparable to the overall reduction of 21% in the risk for a severe exacerbation when a tiotropium inhaler was added to the combination of inhaled glucocorticoids and long-acting beta2 agonist (hazard ratio [HR], 0.79; P = .03) in a previous study (N Engl J Med. 2012 27;367:1198-207).

However, the TRIMARAN and TRIGGER population was much broader, Virchow pointed out. Participants in the 2012 study were selected on the basis of asthma severity and ability to use an inhaler properly.

In a pooled analysis of TRIMARAN and TRIGGER, time to moderate or severe exacerbation was longer with single-inhaler beclometasone, formoterol, and glycopyrronium than with the two-drug combination of beclometasone and formoterol (HR, 0.82; P = .0002), as were time to first moderate exacerbation (HR, 0.83; P = .0010) and time to first severe exacerbation (HR, 0.79; P = .011.)

"The results are statistically significant but not extremely impressive. Remember that if you have normal lung function, your room for improvement is very small," Virchow said.

One must keep in mind that these are controlled clinical studies, "but we do think that real-world patients on triple therapy will have better adherence with one inhaler," Virchow said.

Triple therapy is already known to improve lung function and improve exacerbations, but the need for two inhalers to deliver the medicine can "lead to several potential problems," he explained.

"There are good data showing that more inhalers mean more errors in usage," he added.

More Inhalers, More Errors

First, a different technique is needed for the two inhalers. "One is a mist that requires the user to inhale very slowly and deeply," he explained. The other, a powder, requires the patient to suck more forcefully.

Second, patients can develop preferences and might skip the inhaler they don't like or don't think is working for them. A long-acting muscarinic antagonist can take about 45 minutes to work, so patients do not feel any immediate benefit, said Virchow.

Third, the capacity of inhalers is different, so prescriptions are not necessarily refilled at the same time.

"You can imagine all the scenarios," he said. "We expect that patients in the real world needing triple therapy will have better adherence with a single inhaler."

But even with one inhaler, patients need to be educated regularly on proper technique, said Luc Steenhuis, PhD, MD, from Martini Hospital, Groningen, Netherlands.

He and his colleagues were prompted to look at the effectiveness of inhaler training after an assessment of COPD patients showed that only 8% were using their inhaler correctly.

In their study, 1 year after patients underwent education and received a card to take home that depicts proper use, 66% of patients had an "adequate" technique, Steenhuis reported during a poster session at the congress.

"When you don't use it properly, it won't work," he said. "All your expensive medication and research doesn't help when the medicine goes into the air; it has to go into the patient's lungs."

Steenhuis said his group now give a visual inhaler card to all patients prescribed an inhaler, "and we think we need to repeat training once a year."

A Cost-effective Choice

Patients with severe asthma who do not have access to biologics can benefit from triple therapy, said Mark FitzGerald, MD, from Vancouver General Hospital, in Canada, who was involved in the TRIMARAN and TRIGGER study.

"Forty percent of patients on a combination therapy remain uncontrolled, with excessive exposure to systemic prednisone," he explained. "Before you go to a biologic, for about three-quarters of these patients, a triple therapy is the best most cost-effective choice."

For patients with uncontrolled asthma who don't have direct access to biologics, "you don't have to be an economist to understand that tiotropium, although less effective, is much cheaper."

"And the fact that they're using one inhaler simplifies it for the patient and the physician," said FitzGerald.

Still, for some patients with severe asthma and exacerbations, "one could consider skipping to biologics without embarking on a triple-combination inhaler. I don't think this should preclude earlier use of biologics, especially in patients with frequent exacerbations and elevated peripheral eosinophil counts," he added.

Virchow reports financial relationships with AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi Farmaceutici, Deutsche Forschungsgesellschaft, Essex/Schering-Plough, Gemeinsame Bundesausschuss, GlaxoSmithKline, Janssen-Cilag, Land Mecklenburg-Vorpommern, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Paul-Ehrlich Institut, Regeneron Revotar, Roche, Sanofi-Aventis, Sanofi/Regeneron, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila. Steenhuis has disclosed no relevant financial relationships. FitzGerald reports financial relationships with AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Sanofi Regeneron.

European Respiratory Society (ERS) 2019 International Congress. Poster PA1479, presented September 29, 2019; Abstract RCT3779, presented October 1, 2019.

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