Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

Ferguson, Gary T.; Rabe, Klaus F.; Martínez, Fernando J.; Fabbri, Leonardo M.; Wang, Chen; Ichinose, Masakazu; Bourne, Eric; Ballal, Shaila; Darken, Patrick; DeAngelis, Kiernan; Aurivillius, Magnus; Dorinsky, Paul; Reisner, Colin

doi:10.1016/s2213-2600(18)30327-8

Cited by 265 publications

(394 citation statements)

References 26 publications

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“…The KRONOS trial conducted by Ferguson et al showed significant improvement of baseline pre‐dose morning trough FEV1. This improvement was more significant when triple therapy was compared to ICS/LABA over LAMA/LABA, which is consistent with our study results . These objective results are supported by the SGRQ responders for assessing the quality of life in those with moderate‐to‐severe COPD.…”

Section: Discussionsupporting

confidence: 86%

“…A comprehensive electronic database search provided 1,139 studies for review, and manual search identified 39 additional studies. After review, 12 RCTs comparing triple inhaler therapy with dual inhaler therapy in patients with moderate‐to‐severe COPD remained and were included in the analysis . We have excluded trials that evaluated the de‐escalation of triple therapy to dual therapy as patients in both treatment arms received triple inhaler before de‐escalation to dual therapy which could affect the results .…”

Section: Resultsmentioning

confidence: 99%

“…We have excluded trials that evaluated the de‐escalation of triple therapy to dual therapy as patients in both treatment arms received triple inhaler before de‐escalation to dual therapy which could affect the results . In the study performed by Ferguson et al, patients who received budesonide and formoterol therapy as a metered dose inhaler, not open label inhaler, were included in ICS/LABA group . The RCT selection process is shown in Figure .…”

Section: Resultsmentioning

confidence: 99%

“…The OUTPUL study was neither randomized nor controlled, which increased the risk of bias and confounding variables that may have affected the results. Furthermore, the KRONOS (Randomized, Double‐Blind, Parallel‐Group, 24‐Week, Chronic‐Dosing, Multi‐Center Study to Assess the Efficacy and Safety of PT010, PT003 and PT009 Compared With Symbicort® Turbuhaler® as an Active Control in Subjects with Moderate to Very Severe COPD) trial showed reduction of moderate‐to‐severe COPD exacerbations with triple therapy consisting of budesonide, glycopyrrolate and formoterol fumarate in comparison to LABA/LAMA (glycopyrrolate and formoterol fumarate), but not dual therapy ICS/LABA (budesonide and formoterol) . These findings oppose the IMACT and TRILOGY (Efficacy of Fixed Combination of Beclometasone + Formoterol +Glycopyrrolate Versus Foster® in COPD) trials which had shown significant reduction in COPD exacerbations with triple therapy compared to ICS/LABA .…”

Section: Discussionmentioning

confidence: 99%

“…After review, 12 RCTs comparing triple inhaler therapy with dual inhaler therapy in patients with moderate-to-severe COPD remained and were included in the analysis. [11][12][13][14][15][16][17][18][19][20] We have excluded trials that evaluated the de-escalation of triple therapy to dual therapy as patients in both treatment arms received triple inhaler before de-escalation to dual therapy which could affect the results. 21,22 In the study performed by Ferguson et al, patients who received budesonide and formoterol therapy as a metered dose inhaler, not open label inhaler, were included in ICS/ LABA group.…”

Section: Summary Of the Studiesmentioning

confidence: 99%

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Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials

Zayed

Barbarawi

Kheiri

et al. 2019

Clinical Respiratory J

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Introduction Treatment of chronic obstructive pulmonary disease (COPD) is evolving specially with triple inhaler therapy. Objectives To perform a meta‐analysis to ascertain the safety and efficacy of triple inhaler therapy consisting of an inhaled‐glucocorticoid (ICS), long‐acting muscarinic antagonist (LAMA) and long‐acting beta2‐agonist (LABA) when compared with dual therapy (ICS‐LABA or LAMA‐LABA). Methods We performed an electronic database search to include randomized controlled trials (RCTs) comparing between triple and dual inhalers. Pooled rate‐ratio (RR) or odds‐ratio (OR) for dichotomous data and weighted mean difference (MD) for continuous data were calculated with their corresponding 95% confidence interval (CI). Results Our study included 12 RCTs totaling 19,322 patients, mean age of 65 ± 8.2 years and 68.2% were male. Pooled analysis demonstrated a significant reduction in moderate‐to‐severe COPD exacerbations with triple therapy (RR 0.75; 95% CI 0.69‐0.83; P < 0.01). Additionally, triple therapy caused significant increase in trough FEV1 (MD 0.09 L; 95% CI 0.07‐0.12; P < 0.01), significant reduction in the mean St. George's Respiratory Questionnaire (SGRQ) score (MD −1.67; 95% CI −2.02‐ −1.31; P < 0.01), and more patients experienced ≥ 4 points reduction of SGRQ score (OR 1.27; 95% CI 1.19‐1.35; P < 0.01). Triple therapy was associated with an increased risk of pneumonia when compared to LABA/LAMA (OR 1.25; 95% 1.03‐1.97; P = 0.03) but there were no significant differences in other adverse events between triple and dual inhalers. Conclusions Among patients with moderate‐to‐severe COPD, triple inhaler therapy was associated with a reduction of moderate‐to‐severe COPD exacerbations, improved lung function and improved quality of life when compared to dual inhaler therapy but with an increased pneumonia risk.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Summary Of the Studiesmentioning

confidence: 99%

See 3 more Smart Citations

Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials

Zayed

Barbarawi

Kheiri

et al. 2019

Clinical Respiratory J

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Diagnosis and Outpatient Management of Chronic Obstructive Pulmonary Disease

Riley

Sciurba

2019

JAMA

160

110

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CONCLUSIONS AND RELEVANCE Chronic obstructive pulmonary disease is a complicated disease requiring intensive treatment. Appropriate use of long-acting maintenance bronchodilators, inhaled corticosteroids, and pulmonary rehabilitation decreases symptoms, optimizes functional performance, and reduces exacerbation frequency. Supplemental oxygen in patients with resting hypoxemia prolongs life, and other advanced treatments are available based on specific patient characteristics.

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Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease

van Geffen,

Tan,

Walters

et al. 2023

Cochrane Database of Systematic Reviews

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Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

Cited by 265 publications

References 26 publications

Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials

Triple versus dual inhaler therapy in moderate‐to‐severe COPD: A systematic review and meta‐analysis of randomized controlled trials

Diagnosis and Outpatient Management of Chronic Obstructive Pulmonary Disease

Inhaled corticosteroids with combination inhaled long-acting beta2-agonists and long-acting muscarinic antagonists for chronic obstructive pulmonary disease

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