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The TRINITY study: Twitter discussion from a respirology journal club – Authors' reply
Correspondence
The TRINITY study: Twitter discussion from a respirology journal club Authors’ reply
We would like to thank Anju Anand and colleagues for their interest in our recent paper.1 First, we can confirm that all treatments were double-blind, achieved by using a double-dummy approach. The use of the phrase open triple was shorthand used throughout the manuscript to indicate the use of inhaled corticosteroids and a long-acting β agonist in one inhaler and long-acting muscarinic agonist in a second, whereas fixed triple indicates that the three active treatments were in one inhaler (with placebo administered in the second). Second, compliance is unlikely to explain any differences between groups, not only because a double-dummy approach was used (with all patients using one inhaler twice daily and the other inhaler once daily), but compliance was high in all treatment groups (median compliance of 94·6% for fixed triple, 94·3% for tiotropium, and 94·9% for open triple). It is possible that the use of a single inhaler triple combination could improve adherence or compliance in real-world settings, but interventional clinical trials cannot
www.thelancet.com/respiratory Vol 5 July 2017
provide such evidence. We decided to assess compliance using an electronic diary, since the device could capture much more information than is possible through a capsule count or canister weight (which are the most common alternatives in interventional clinical trials), especially in view of the differences in dosing regimens for the two inhalers. The authors raise an interesting point about ICS withdrawal. This is a possibility, but if this was the case we would anticipate seeing some initial destabilisation in the two triple therapy groups—and the lines in the Kaplan-Meier figure (figure 2B)1 are straight, suggesting that this wasn’t the case. Additionally, withdrawal was highest in the tiotropium group and as we know from other studies that poor health status and exacerbations are associated with risk of withdrawal, this might have affected exacerbation rates later in the study. Finally, we fully agree that the eosinophil results in TRINITY are consistent with other analyses, and that other trials are warranted that examine the relative efficacy of LABA/LAMA versus triple therapy. JV reports personal fees from Chiesi Farmaceutici during the conduct of the study; outside of the submitted work, he reports personal fees from GlaxoSmithKline, Chiesi Farmaceutici, BoehringerIngelheim, Novartis, and AstraZeneca.
Jørgen Vestbo, on behalf of the TRINITY investigators [email protected] Division of Infection, Immunity, and Respiratory Medicine, University of Manchester, Manchester M13 9NT, UK. 1
Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic-obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389: 1919–29.
Corrections Beigel JH, Teblas P, Elie-Turenne M-C, et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med 2017; 5: 500–11—In the appendix, the affiliation for Janine Danko has been amended to “Walter Reed National Military Medical Center, Bethesda, MD” and Donald Siegel, Faye DeMuth, Craig H Fletcher, J Peter R Pelletier, Hassan Alnuaimat, and Michelle Pourde have been added to the IRC002 Study Team. These corrections have been made to the online version as of June 23, 2017. Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; 1: 630–38—In table 2 of this Article, the median data for lung clearance index at baseline and day 15 were incorrect. This correction has been made to the online version as of June 23, 2017.
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The TRINITY study: Twitter discussion from a respirology journal club Authors’ reply
We would like to thank Anju Anand and colleagues for their interest in our recent paper.1 First, we can confirm that all treatments were double-blind, achieved by using a double-dummy approach. The use of the phrase open triple was shorthand used throughout the manuscript to indicate the use of inhaled corticosteroids and a long-acting β agonist in one inhaler and long-acting muscarinic agonist in a second, whereas fixed triple indicates that the three active treatments were in one inhaler (with placebo administered in the second). Second, compliance is unlikely to explain any differences between groups, not only because a double-dummy approach was used (with all patients using one inhaler twice daily and the other inhaler once daily), but compliance was high in all treatment groups (median compliance of 94·6% for fixed triple, 94·3% for tiotropium, and 94·9% for open triple). It is possible that the use of a single inhaler triple combination could improve adherence or compliance in real-world settings, but interventional clinical trials cannot
www.thelancet.com/respiratory Vol 5 July 2017
provide such evidence. We decided to assess compliance using an electronic diary, since the device could capture much more information than is possible through a capsule count or canister weight (which are the most common alternatives in interventional clinical trials), especially in view of the differences in dosing regimens for the two inhalers. The authors raise an interesting point about ICS withdrawal. This is a possibility, but if this was the case we would anticipate seeing some initial destabilisation in the two triple therapy groups—and the lines in the Kaplan-Meier figure (figure 2B)1 are straight, suggesting that this wasn’t the case. Additionally, withdrawal was highest in the tiotropium group and as we know from other studies that poor health status and exacerbations are associated with risk of withdrawal, this might have affected exacerbation rates later in the study. Finally, we fully agree that the eosinophil results in TRINITY are consistent with other analyses, and that other trials are warranted that examine the relative efficacy of LABA/LAMA versus triple therapy. JV reports personal fees from Chiesi Farmaceutici during the conduct of the study; outside of the submitted work, he reports personal fees from GlaxoSmithKline, Chiesi Farmaceutici, BoehringerIngelheim, Novartis, and AstraZeneca.
Jørgen Vestbo, on behalf of the TRINITY investigators [email protected] Division of Infection, Immunity, and Respiratory Medicine, University of Manchester, Manchester M13 9NT, UK. 1
Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic-obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet 2017; 389: 1919–29.
Corrections Beigel JH, Teblas P, Elie-Turenne M-C, et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med 2017; 5: 500–11—In the appendix, the affiliation for Janine Danko has been amended to “Walter Reed National Military Medical Center, Bethesda, MD” and Donald Siegel, Faye DeMuth, Craig H Fletcher, J Peter R Pelletier, Hassan Alnuaimat, and Michelle Pourde have been added to the IRC002 Study Team. These corrections have been made to the online version as of June 23, 2017. Davies J, Sheridan H, Bell N, et al. Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial. Lancet Respir Med 2013; 1: 630–38—In table 2 of this Article, the median data for lung clearance index at baseline and day 15 were incorrect. This correction has been made to the online version as of June 23, 2017.
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