Elsevier

The Lancet

Volume 394, Issue 10210, 9–15 November 2019, Pages 1737-1749
The Lancet

Articles
Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials

https://doi.org/10.1016/S0140-6736(19)32215-9Get rights and content

Summary

Background

To date, no studies have assessed the efficacy of single-inhaler triple therapy in asthma. Here we report on two studies that compared the single-inhaler extrafine combination of beclometasone dipropionate (BDP; inhaled corticosteroid), formoterol fumarate (FF; long-acting β2 agonist), and glycopyrronium (G; long-acting muscarinic antagonist) with the combination of BDP with FF.

Methods

Two parallel-group, double-blind, randomised, active-controlled, phase 3 trials (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) recruited patients from 171 sites across 16 countries (TRIMARAN), and from 221 sites across 17 countries (TRIGGER). The sites were a mixture of secondary and tertiary care centres and specialised investigation units. Eligible patients were adults (aged 18–75 years) with uncontrolled asthma, a history of one or more exacerbations in the previous year, and previously treated with inhaled corticosteroid (TRIMARAN: medium dose; TRIGGER: high dose) plus a long-acting β2 agonist. Enrolled patients were initially treated with BDP/FF (TRIMARAN: 100 μg BDP and 6 μg FF; TRIGGER: 200 μg BDP and 6 μg FF) for 2 weeks, then randomly assigned to treatment using an interactive response technology system with a balanced block randomisation scheme stratified by country. Patients, investigators, site staff, and sponsor staff were masked to BDP/FF/G and BDP/FF assignment. In TRIMARAN, patients were randomly assigned (1:1) to 52 weeks of BDP/FF/G (100 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (100 μg BDP and 6 μg FF), two inhalations twice daily. In TRIGGER, patients were randomly assigned (2:2:1) to 52 weeks of BDP/FF/G (200 μg BDP, 6 μg FF, and 10 μg G) or BDP/FF (200 BDP and 6 μg FF), both two inhalations twice daily, or open-label BDP/FF (200 μg BDP and 6 μg FF) two inhalations twice daily plus tiotropium 2·5 μg two inhalations once daily. Coprimary endpoints for both trials (BDP/FF/G vs BDP/FF) were pre-dose forced expiratory volume in 1 s (FEV1) at week 26 and rate of moderate and severe exacerbations over 52 weeks. Safety was assessed in all patients who received at least one dose of study treatment. These trials were registered with ClinicalTrials.gov, NCT02676076 (TRIMARAN), NCT02676089 (TRIGGER).

Findings

Between Feb 17, 2016, and May 17, 2018, 1155 patients in TRIMARAN were given BDP/FF/G (n=579) or BDP/FF (n=576). Between April 6, 2016, and May 28, 2018, 1437 patients in TRIGGER were given BDP/FF/G (n=573), BDP/FF (n=576), or BDP/FF plus tiotropium (n=288). Compared with the BDP/FF group, week 26 predose FEV1 improved in the BDP/FF/G group by 57 mL (95% CI 15–99; p=0·0080) in TRIMARAN and by 73 mL (26–120; p=0·0025) in TRIGGER, with reductions in the rate of moderate and severe exacerbations of 15% (rate ratio 0·85, 95% CI 0·73–0·99; p=0·033) in TRIMARAN and 12% (0·88, 0·75–1·03; p=0·11) in TRIGGER. Four patients had treatment-related serious adverse events, one in TRIMARAN in the BDP/FF/G group and three in TRIGGER—one in the BDP/FF/G and two in the BDP/FF group. Three patients in the BDP/FF/G group in TRIMARAN and two patients in TRIGGER—one in the BDP/FF/G group and one in the BDP/FF group—had adverse events leading to death. None of the deaths were considered as related to treatment.

Interpretation

In uncontrolled asthma, addition of a long-acting muscarinic antagonist to inhaled corticosteroid plus long-acting β2-agonist therapy improves lung function and reduces exacerbations.

Funding

Chiesi Farmaceutici.

Introduction

Goals of asthma management are to achieve symptom control and avoid future risks, especially risks of exacerbations.1 Asthma is characterised by the presence of chronic airway inflammation; hence inhaled corticosteroids are the mainstay of therapy.1 Many patients are able to achieve good disease control, especially from an inhaled corticosteroid plus long-acting β2 agonist combination.2 However, until recently, few options were available for patients who could not achieve controlled asthma with such combinations.

Research in context

Evidence before this study

We searched PubMed for articles published from database inception until April 4, 2019, using the search term “drug therapy, combination’ [MeSH terms] OR triple AND asthma AND trial NOT theophylline NOT montelukast, with no restrictions. Of the 1068 hits, eight articles presented data from clinical trials that assessed the efficacy of triple therapy comprising an inhaled corticosteroid plus a long-acting β2 agonist plus a long-acting muscarinic antagonist. Of these articles, six reported data in adults (the other two reported data in children or adolescents), of which one article was a short-term (4-week) study, one reported pooled safety data, and one reported subgroup analyses of studies presented in another manuscript. The remaining three articles reported data from studies in which the long-acting muscarinic antagonist tiotropium was added as a free combination to any inhaled corticosteroid and long-acting β2 agonist. The first of these articles presented data from two 48-week studies, in which the addition of tiotropium to high-dose inhaled corticosteroid plus a long-acting β2 agonist delayed the time to first asthma exacerbation and reduced the overall risk of these events, with improvements in lung function. The second article focused on the long-term (52-week) safety profile of the addition of tiotropium to inhaled corticosteroid plus a long-acting β2 agonist, which was similar to inhaled corticosteroid plus a long-acting β2 agonist alone. In the third article, the addition of tiotropium improved airflow and reduced airway wall thickness after 48 weeks. All three studies assessed the effect of tiotropium plus inhaled corticosteroid plus long-acting β2-agonist therapy in patients with spirometrically assessed persistent airflow limitation (ie, ratio of forced expiratory volume in 1 s to forced vital capacity <0·7).

Added value of this study

TRIMARAN and TRIGGER are the first studies to assess the efficacy and safety of single-inhaler triple therapy compared with inhaled corticosteroid plus a long-acting β2 agonist in adults with asthma. Additionally, these are the first long-term studies undertaken in patients who had no requirement to show persistent airflow limitation after short-acting β2 agonist use.

Implications of all the available evidence

The combination of a long-acting muscarinic antagonist with an inhaled corticosteroid plus long-acting β2-agonist therapy in adults with uncontrolled asthma results in improved lung function. In large, long-term studies, triple therapy has a positive effect on severe exacerbations.

The addition of the long-acting muscarinic antagonist tiotropium to inhaled corticosteroid plus long-acting β2-agonist therapy has been shown to improve lung function and, in longer studies (48-week duration), reduce the risk of exacerbations in patients with asthma, although in a subgroup of patients with persistent airflow limitation.3, 4, 5 However, the addition of tiotropium requires patients to use two different inhalers of different design with different instructions for use, and often with different dosing regimens. Such a combination is not only inconvenient for patients and health-care providers who instruct on correct inhaler use, but can negatively affect treatment adherence and persistence.6, 7, 8, 9 A single-inhaler triple therapy consisting of an extrafine formulation (ie, with mass median aerodynamic diameter <2 μm) of the inhaled corticosteroid beclometasone dipropionate, the long-acting β2 agonist formoterol fumarate, and the long-acting muscarinic antagonist glycopyrronium (known as BDP/FF/G from hereon) delivered via a pressurised metered-dose inhaler is in development for patients with asthma. Such extrafine formulations result in improved deposition in the small airways,10 which is potentially important given that patients with asthma with substantial dysfunction of the small airways tend to have worse asthma control and quality of life and are at increased exacerbation risk.11

In this Article, we report the results of two phase 3, 52-week studies (Triple in Asthma With Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN] and Triple in Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]) comparing the efficacy and safety of medium-strength (TRIMARAN) and high-strength (TRIGGER) BDP/FF/G with that of the medium-strength (TRIMARAN) and high-strength (TRIGGER) beclometasone dipropionate plus formoterol fumarate (BDP/FF) in patients with asthma that is poorly controlled on medium-dose (TRIMARAN) or high-dose (TRIGGER) inhaled corticosteroid plus long-acting β2 agonist therapy. These are the first studies to assess single-inhaler triple therapy in a broad asthma population not restricted to those with persistent airflow limitation.

Section snippets

Study design and participants

TRIMARAN and TRIGGER were both randomised, parallel-group, double-blind, active-controlled phase 3 studies. The main difference between the studies was the inhaled corticosteroid dose received before and during the study, with patients in TRIMARAN receiving a medium dose and patients in TRIGGER receiving a high dose.

Patients were recruited for TRIMARAN from 171 sites across 16 countries, and for TRIGGER patients were recruited from 221 sites across 17 countries (countries listed in the appendix

Results

TRIMARAN was undertaken between Feb 17, 2016, and May 17, 2018, during which time 1628 patients were assessed for eligibility, of whom 1155 patients were randomly assigned to the BDP/FF/G group (n=579) or the BDP/FF group (n=576); 542 (94%) patients in the BDP/FF/G group and 539 (94%) in the BDP/FF group completed treatment (figure 1A). TRIGGER was undertaken between April 6, 2016, and May 28, 2018, during which time 2100 patients were assessed for eligibility, of whom 1437 were randomly

Discussion

TRIMARAN and TRIGGER are the first studies to assess the efficacy and safety of single-inhaler triple therapy in the management of asthma. The lung function (predose FEV1) coprimary endpoint was met in both studies, with a slightly larger effect size in TRIGGER. Furthermore, the rate of moderate and severe exacerbations coprimary endpoint was met in TRIMARAN, with a significant 15% reduction for BDP/FF/G versus BDP/FF, and although a similar effect size was seen in TRIGGER, with a 12%

Data sharing

Chiesi Farmaceutici is committed to conducting legitimate research and sharing with qualified scientific and medical researchers the anonymised patient-level and study-level data, clinical protocol, and full clinical study report of Chiesi Farmaceutici sponsored interventional clinical trials in patients for medicines and indications approved by the European Medicines Agency or the US Food and Drug Administration, or both, after Jan 1, 2015, following the approval of any received research

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