For the second time, Chiesi’s extra fine fixed ICS/LABA/LAMA triple combination therapy wins a place in the pages of 'The Lancet', with the publication of the TRINITY study conducted by Chiesi.

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Date: 04/01/2017

São Paulo, April 4, 2017 - Today, The Lancet published the results of the TRINITY study1, which for the first time demonstrated the superiority of extrafine fixed ICS/LABA/LAMA triple combination, developed by Chiesi, compared to tiotropium LAMA, one of the standard treatments for Chronic Obstructive Pulmonary Disease (COPD).

The study led by Jørgen Vestbo, former president of the European Respiratory Society and Professor of Respiratory Medicine at the University of Manchester (UK) and the University of Southern Denmark, was conducted on 2,580 patients over 40 years of age with severe or very severe COPD. Patients were randomized to one of three arms: one treated with fixed dose ICS/LABA/LAMA triple therapy, one with extemporaneous triple therapy (fixed ICS/LABA/LAMA combination therapy plus one LAMA administered with two different inhalers) and a third with the tiotropium LAMA.

Chiesi’s fixed triple combination was superior to tiotropium LAMA during 52 weeks of treatment based on the following clinically and statistically significant effects:

  • Annual rate of moderate and severe exacerbations reduced by 20% after 52 weeks of treatment.
  • Pulmonary function, expressed as FEV 1 (forced expiratory volume in the first second), increased by 61 mL after 52 weeks of treatment.

 

Another important finding is the absence of increased risk of pneumonia associated with the use of inhaled corticosteroids (ICS). In addition, the efficacy and safety of the triple fixed dose combination were not inferior to those of the extemporaneous triple combination, with the additional advantage of using only one device with the three drugs:

  • beclomethasone, an inhaled corticosteroid (ICS) anti-inflammatory agent;
  • formoterol, a long-acting beta-2 agonist (LABA) bronchodilator;
  • glycopyrronium, a long-acting muscarinic antagonist (LAMA) bronchodilator.

 

An additional advantage is provided by the formulation with extra fine particles that allows the active ingredients in both central and small airways to be reached. COPD is characterized by chronic inflammation, causing structural changes, narrowing of the small airways and destruction of the lung parenchyma2. It is estimated that the compromise of the small airways is present in up to 90% of the symptomatic patients with COPD3.

In the TRILOGY4 study published last September in The Lancet, the same fixed-dose triple combination developed by Chiesi had already demonstrated superior efficacy compared to fixed-dose combination therapy with ICS/LABA (a standard treatment for COPD) in a large number of clinical parameters, reducing the annual exacerbation rate by 23%, improving lung function and reducing dyspnea. 

 

 

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Editorial published in The Lancet

The TRINITY study report is accompanied by an editorial5 written by Leonardo M. Fabbri and colleagues. Fabbri is a Professor of Respiratory and Internal Medicine at the University of Modena and Reggio Emilia. The editorial discusses the COPD combination therapy based on newly published results and recently revised treatment guidelines in the 2017 GOLD Report2, the latest issue of the Global Initiative for Chronic Obstructive Lung Disease (GOLD).

"Compared with tiotropium, the triple therapy showed a significant (20%) reduction in the moderate to severe exacerbations rate in COPD along with a significant improvement in lung function (both primary outcomes)" - Professor Fabbri points out - "The study of Vestbo and associates provides for the first time evidence of clinical superiority over LAMA alone, particularly tiotropium, the most studied and clinically effective LAMA, in moderate to severe exacerbations and, significantly without the increased risk of ICS-associated pneumonia, contrary to what was reported in a large real-life study7.

The new GOLD guidelines

In previous versions up to 2016, for patients with severe COPD - symptomatic patients at risk of exacerbations and/or severe airflow limitations, the GOLD guidelines recommended treatment with LAMA or LABA in combination with ICS8.

The 2017 review of the GOLD Report introduced a new classification of disease severity into four categories: ABCD, based on symptoms and history of exacerbation, while lung function assessment is now primarily reserved for confirmation of the diagnosis.

According to Professor Fabbri, the results of TRILOGY and TRINITY provide strong evidence to support the efficacy of triple therapy for COPD patients with severity now defined as Group B: highly symptomatic but at low risk for exacerbations, despite the fact that the new GOLD guidelines recommend long-acting bronchodilators alone or in combination for these patients, but no combination including ICS.

"Undoubtedly," Professor Fabbri concludes, "this classification/recommendation will need to be revised in the 2018 edition of GOLD. And, of course, long-term, randomized clinical trials should be performed with triple therapy in COPD patients in GOLD group B (ie, elderly, fragile, multi-morbid patients who are usually underrepresented in clinical studies). Such studies should have the ambition of including hospitalization and survival as outcomes."

 The new category of patients according to the 2017 GOLD Report

Category A: patients with moderate symptoms, no exacerbations or only one exacerbation not leading to hospitalization.

Category B: patients with more severe symptoms, no exacerbations or only one exacerbation not leading to hospitalization.

Category C: patients with moderate symptoms, at least one exacerbation leading to hospitalization or, in any case, two or more exacerbations.

Category D: patients with more severe symptoms, at least one exacerbation leading to hospitalization or, in any case, two or more exacerbations.

Respiratory function is categorized into four groups with increasing levels of functional limitation and is expressed as GOLD 1, GOLD 2, GOLD 3 and GOLD 4.

References

  1. Vestbo J, Papi A, Corradi M, Blazhko V, Montagna I, Francisco C, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomized controlled trial. thelancet.com Published online April 3, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30567-6
  2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Availbale from goldcopd.org
  3. Crisafulli et al. Prevalence of Small-Airway Dysfunction among COPD Patients with Different GOLD Stages and Its Role in the Impact of Disease, Respiration. 2017;93(1):32-41)
  4. Singh D, Papi A, Corradi M, Pavlisova I, Montagna I, Francisco C, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomized controlled trial. 2016; 388(10048): 963-73
  5. thelancet.com Published online April 3, 2017 http://dx.doi.org/10.1016/S0140-6736(17)30567-6
  6. Halpin DM, Vogelmeier C, Pieper MP, Metzdorf N, Richard F, Anzueto A. Effect of tiotropium on COPD exacerbations: A systematic review. Respiratory medicine. 2016; 114: 1-8
  7. Vestbo J, Leather D, Diar Bakerly N, New J, Gibson JM, McCorkindale S, et al. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice. The New England journal of medicine. 2016; 375(13): 1253-60
  8. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from www.goldcopd.org.