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Single-inhaler triple therapy reduces COPD exacerbations vs dual therapies in ETHOS trial

Prof. Klaus Rabe
University of Kiel
Germany
07 Aug 2020
The phase III ETHOS trial compared the efficacy and safety of two dose levels of single-inhaler, fixed-dose, triple combinations of budesonide/glycopyrrolate/formoterol fumarate (BGF) with dual combinations of glycopyrrolate/formoterol fumarate (GF) and budesonide/formoterol fumarate (BF) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). At the American Thoracic Society 2020 virtual session on clinical trials held recently, lead investigator Professor Klaus Rabe of the University of Kiel, Germany, presented the findings demonstrating superiority of the triple combination regimens over the two dual therapies.

Triple combination therapy for COPD

Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients who experience further exacerbations and/or remain symptomatic on dual ICS/LABA or LAMA/LABA therapy. [Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2020 Report: https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf] 

In the 24-week KRONOS trial, the triple ICS/LAMA/LABA combination of BGF demonstrated benefits on lung function, symptoms and exacerbations vs the dual therapies GFF (LAMA/LABA) and BF (ICS/LABA) in symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history. [Lancet Respir Med 2018;6:747-758]

ETHOS trial

The randomized, double-blind, phase III, 52-week ETHOS trial compared two dose levels of budesonide in BGF (320/18/9.6 μg BID and 160/18/9.6 μg BID) with GFF (18/9.6 μg BID) and BF (320/9.6 μg BID) in 8,509 patients with a history of moderate to very severe COPD exacerbations in the 12 months prior to screening. [Respir Med 2019;158:59-66]

“ETHOS is the first trial of a single-inhaler triple combination therapy that allows direct comparison of two steroid doses for their propensity to reduce exacerbations,” noted Rabe.

“The baseline characteristics, including lung function, therapy at entry and eosinophil counts, were well-matched among the treatment groups,” he added.

BGF triple therapy cuts COPD exacerbations vs LAMA/LABA and ICS/LABA

The primary efficacy endpoint of annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 in the 320 μg-budesonide and 160 μg-budesonide triple therapy groups, and 1.42 and 1.24 in the GFF and BFF groups, respectively. (Figure 1)

HK-AST-412_01

“Triple combination with both budesonide doses resulted in significant reductions of moderate or severe exacerbations vs both dual therapies. The primary endpoint was met for all comparisons,” pointed out Rabe.

The exacerbation rate with 320 μg-budesonide triple therapy was 24 percent lower vs GFF (rate ratio [RR], 0.76; 95 percent confidence interval [CI], 0.69 to 0.83; p<0.001) and 13 percent lower vs BF (RR, 0.87; 95 percent CI, 0.79 to 0.95; p=0.003). Similarly, the rate with 160 μg-budesonide triple therapy was 25 percent lower vs GF (RR, 0.75; 95 percent CI, 0.69 to 0.83; p<0.001) and 14 percent lower vs BF (RR, 0.86; 95 percent CI, 0.79 to 0.95; p=0.002). [N Engl J Med 2020;383:35-48]

Both doses of BGF conferred significant benefits on the secondary endpoint of time to first moderate or severe COPD exacerbation vs both dual therapies (320 μg-budesonide triple therapy vs GF [p=0.004] and BF [p=0.006]; 160 μg-budesonide triple therapy vs GF [p=0.001] and BF [p=0.002]). [N Engl J Med 2020;383:35-48]

“Despite the limited number of severe COPD exacerbations in the trial, a significant benefit was observed for the higher dose of BGF vs BF [p=0.02], with a clear trend favouring triple therapy in the other comparisons,” noted Rabe.

“The superiority of both triple combination regimens over LAMA/LABA in terms of reducing the rate of moderate-to-severe exacerbations was independent of prior ICS use. Therefore, the results were not impacted by some patients’ steroid withdrawal at trial entry,” he clarified.

Higher-dose budesonide triple regimen reduces all-cause death vs LAMA/LABA

“Time to all-cause mortality, a key secondary endpoint, demonstrated a graded response over 52 weeks, with GF showing the highest mortality and the higher-dose budesonide triple therapy showing the lowest mortality,” said Rabe.

Notably, patients treated with 320 μg-budesonide triple therapy had a 46 percent reduction in risk of death from any cause vs those treated with GF (hazard ratio, 0.54; 95 percent CI, 0.34 to 0.87; punadjusted =0.01). (Figure 2) [N Engl J Med 2020;383:35-48]

HK-AST-412_02

Both doses of budesonide triple therapy improved symptoms and QoL

Clinically and statistically highly significant benefits in several secondary symptoms and quality of life (QoL) endpoints were observed with both doses of budesonide triple therapy vs dual therapies (p<0.0001 to p=0.0127). These included change from baseline in rescue medication use, Transition Dyspnoea Index (TDI) focal score, change from baseline in Exacerbations of COPD Tool (EXACT) total score, change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score, and percentage of patients achieving the minimum clinically important difference (MCID) in SGRQ total score. [N Engl J Med 2020;383:35-48]

“Triple therapy with 160 µg of budesonide showed greater efficacy in terms of exacerbation and QoL endpoints vs the dual therapy with twice the steroid dose [ie, BF], allowing steroid dose reduction in patients with COPD,” Rabe pointed out. “These data should inform the medical community on the role of the lower-dose triple drug combination.”

AEs of BGF consistent with safety profile of components

There were no differences between the four treatment groups in terms of adverse events (AEs) that led to treatment discontinuation. The incidence of pneumonia was higher in the groups receiving an ICS (3.5–4.5 percent) vs GF (2.3 percent). Conversely, major adverse cardiovascular events occurred more frequently in patients receiving GF (2.1 percent) relative to the other groups (1.1–1.4 percent).

Summary

Triple BGF combination therapy with either 320 µg or 160 µg of budesonide significantly reduced the rate of moderate or severe COPD exacerbations and improved symptoms and health-related QoL vs GF or BF. BGF triple therapy with the higher budesonide dose also reduced all-cause mortality by 46 percent vs GF. Furthermore, the lower budesonide dose triple therapy showed greater efficacy than the higher-dose dual therapy, and can be considered an effective treatment option for COPD.

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Most Read Articles
Roshini Claire Anthony, 14 Sep 2020

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