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

Virchow, J. Christian; Kuna, Piotr; Paggiaro, Pierluigi; Papi, Alberto; Singh, Dave; Corre, Sandrine; Zuccaro, Florence; Vele, Andrea; Kots, Maxim; Georges, George; Petruzzelli, Stefano; Canonica, Giorgio Walter

doi:10.1016/s0140-6736(19)32215-9

Cited by 134 publications

(192 citation statements)

References 27 publications

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“…41 Virchow and their colleagues also showed the beneficial effect of GLY on ICS/LABA in uncontrolled asthma. 42 The BUD administered in this study is an ICS retained in airway tissue for longer than other inhaled steroids, resulting in significant prolongation of the anti-inflammatory effect. 43,44 Moreover, FORM is a LABA with a rapid onset of action and a duration of effect of at least 12 hrs.…”

Section: Discussionmentioning

confidence: 97%

<p>Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap</p>

Ishiura

Fujimura

Ohkura

et al. 2020

COPD

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Purpose: Asthma-chronic obstructive pulmonary disease overlap (ACO), characterized by airway limitation, is an important condition with high incidence and mortality. Although some guidelines recommend triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β 2 agonists, this treatment approach is based on the extrapolation of data from studies of asthma or chronic obstructive pulmonary disease (COPD) alone. Methods: A 12-week, randomized, open-label cross-over pilot study was conducted in 19 patients with ACO to investigate the effect of triple therapy with glycopyrrolate (GLY) 50 µg/ day on budesonide/formoterol fumarate (BUD/FORM) 640/18 µg/day. The study period included a 4-week wash-out, 4-week run-in, and 4-week treatment period. Respiratory function tests, fractional exhaled nitric oxide (FeNO), a COPD assessment test (CAT) and an asthma control questionnaire (ACQ) were carried out 0, 4, and 8 weeks after randomization. Results: A total of 19 patients with stable ACO (19 males and no females) with a mean age of 70.7 ± 7.6 years (± standard deviation, SD; range 55-83 years) participated in this study. All patients were ex-smokers with a smoking history of 63.1 ± 41.1 pack-years (± SD). Mean values for inspiratory capacity (IC), an index of hyperinflation of the lung that causes exertional dyspnea and reduced exercise, were 1.93 L (± 0.47 L) after the run-in, 1.85 L (± 0.51 L) after the BUD/ FORM dual therapy period and 2.11 L (± 0.58 L) after the BUD/GLY/FORM triple therapy period. IC values after the BUD/GLY/FORM triple therapy were significantly higher than those after the run-in (p < 0.02). FeNO values, ACQ, and CAT scores were not significantly different among the run-in, wash-out, and triple-therapy periods. Conclusion: The present pilot study showed that triple therapy with BUD/GLY/FORM results in an improvement in lung function parameters including IC, indicating the potential value of triple therapy as standard treatment for ACO.

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Section: Discussionmentioning

confidence: 97%

<p>Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap</p>

Ishiura

Fujimura

Ohkura

et al. 2020

COPD

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“…The full design and inclusion/exclusion criteria of TRIMARAN and TRIGGER have been previously published [ 14 ]. Both studies recruited populations aged 18–75 years, inclusive, with a documented history of asthma for at least one year and diagnosed prior to the age of 40 years, pre-bronchodilator FEV 1 < 80% of the predicted normal value, and a change in FEV 1 of > 12% and > 200 mL 10–15 min after inhaling salbutamol 400 µg.…”

Section: Methodsmentioning

confidence: 99%

“…Such extrafine formulations result in improved deposition in the small airways [ 12 ], which is potentially important given that asthma patients with significant small airways dysfunction tend to have poorer asthma control and quality of life, and are at increased exacerbation risk [ 13 ]. TRIMARAN and TRIGGER were two double-blind, Phase III, 52-week studies comparing the efficacy and safety of medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with that of the respective strengths of BDP/FF in patients with asthma that was poorly controlled on medium-dose (TRIMARAN) or high-dose (TRIGGER) ICS/LABA therapy, with TRIGGER including a third arm in which patients received open-label BDP/FF + tiotropium [ 14 ]. Overall, BDP/FF/G improved lung function [pre-dose and peak forced expiratory volume in 1 s (FEV 1 ) and peak expiratory flow (PEF)] versus BDP/FF in both studies, with significant reductions in the rate of severe exacerbations in a pre-specified pooled analysis.…”

Section: Introductionmentioning

confidence: 99%

Determinants of response to inhaled extrafine triple therapy in asthma: analyses of TRIMARAN and TRIGGER

et al. 2020

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Background A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. Methods These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). Results Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. Conclusion Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1)

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“…These ICS/LABA combinations are not only more effective than ICS monotherapies, but also safe (in contrast to LABA monotherapies) [21]. In the last years, long-acting muscarinic antagonists (LAMA), such as tiotropium, were approved as add-on bronchodilators for asthma treatment, either in separate inhalers or as a single inhaler triple therapy (ICS/LABA/LAMA) [22]. − In 1997, as another anti-inflammatory "controller," the oral leukotriene receptor antagonist (LTRA) montelukast was approved for asthma treatment [23].…”

Section: History Of Asthma Pharmacologymentioning

confidence: 99%

Immune Modulation in Asthma: Current Concepts and Future Strategies

Lommatzsch¹

2020

Respiration

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Asthma treatment concepts have profoundly changed over the last 20 years, from standard therapeutic regimens for all patients with asthma towards individually tailored interventions targeting treatable traits ("precision medicine"). A precise and highly effective immune modulation with minimal adverse effects plays a central role in this new concept. Recently, there have been major advances in the treatment of asthma with immune-modulatory compounds. One example is the approval of several highly potent biologics for the treatment of severe asthma. New immune-modulatory strategies are expected to enter clinical practice in the future; these innovations will be especially important for patients with treatment-resistant asthma.

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

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

Cited by 134 publications

References 27 publications

<p>Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap</p>

<p>Triple Therapy with Budesonide/Glycopyrrolate/Formoterol Fumarate Improves Inspiratory Capacity in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap</p>

Determinants of response to inhaled extrafine triple therapy in asthma: analyses of TRIMARAN and TRIGGER

Immune Modulation in Asthma: Current Concepts and Future Strategies

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