The Lancet MARCH 17, 2018

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial

Papi A, Vestbo J, Fabbri L, et al.

Bottom Line

The TRIBUTE trial demonstrated that a single-inhaler triple therapy (extra-fine beclometasone, formoterol, and glycopyrronium) reduced the annual rate of moderate-to-severe COPD exacerbations compared to a dual bronchodilator regimen (indacaterol and glycopyrronium) in patients with severe-to-very-severe COPD.

Key Findings

1. The primary endpoint was met, with triple therapy demonstrating a 15.2% reduction in the annual rate of moderate-to-severe COPD exacerbations compared to the dual bronchodilator comparator (0.50 per patient per year versus 0.59 per patient per year; rate ratio 0.848; 95% CI 0.723–0.995; p=0.043).

2. The incidence of moderate-to-severe exacerbations was consistently lower in the triple therapy group across the 52-week study period.

3. Adverse event profiles were similar between the treatment arms, with 64% of patients in the triple therapy group and 67% in the dual bronchodilator group reporting at least one adverse event.

4. The risk of pneumonia did not significantly differ between groups, occurring in 4% of participants in the triple therapy arm compared to 4% in the dual bronchodilator arm.

Study Design

Design

RCT

Double-Blind

Sample

1,532

Patients

Duration

52 wk

Median

Setting

Multicenter, 17 countries

Population Patients with symptomatic COPD, severe or very severe airflow limitation (GOLD grade 3–4), and at least one moderate or severe exacerbation in the previous year.

Intervention Extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium (87 μg/5 μg/9 μg) twice daily.

Comparator Indacaterol and glycopyrronium (85 μg/43 μg) once daily.

Outcome Rate of moderate-to-severe COPD exacerbations across 52 weeks.

Study Limitations

• The study duration of 52 weeks is relatively short for assessing long-term safety and disease-modifying effects in a chronic, progressive condition like COPD.

• The trial abruptly discontinued prior inhaled corticosteroid (ICS) maintenance therapy in the study population during the run-in period, which may have influenced the exacerbation rates in the early weeks of the study.

• The population was limited to those with severe to very severe airflow limitation (GOLD 3-4), which may limit the generalizability of these findings to patients with milder disease.

• As a industry-funded trial comparing a specific triple combination, the results may be specific to the extrafine formulation used.

Clinical Significance

The TRIBUTE trial provides evidence supporting the escalation to triple therapy for patients with symptomatic, severe-to-very-severe COPD who remain at risk of exacerbations despite dual bronchodilation. It reinforces the role of triple therapy in reducing exacerbation frequency without a signal for increased pneumonia risk in this specific high-risk cohort.

Historical Context

The TRIBUTE trial was part of a pivotal clinical development program evaluating the efficacy and safety of a single-inhaler extrafine triple therapy (BDP/FF/G). It complemented earlier studies (TRILOGY and TRINITY) by head-to-head comparison against an active dual-bronchodilator control, addressing a significant evidence gap in the stepwise management of COPD defined by global guidelines at the time.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for using 'extra-fine' particles in the triple therapy formulation used in the TRIBUTE trial, and how does this address the pathology of COPD?

Key Response

COPD is characterized by inflammation and remodeling in the small airways (less than 2 mm in diameter), often called the 'silent zone.' Extra-fine formulations (mass median aerodynamic diameter < 2 xm) achieve higher peripheral lung deposition compared to standard particles, allowing the ICS (beclometasone) and bronchodilators to reach the distal sites of airflow obstruction and inflammation more effectively.

Resident

A patient with COPD remains symptomatic with frequent exacerbations despite being on Indacaterol/Glycopyrronium. Based on TRIBUTE, what is the expected clinical benefit of switching to a single-inhaler triple therapy (BDP/FF/GB)?

Key Response

The TRIBUTE trial demonstrated that switching from dual bronchodilation (LAMA/LABA) to single-inhaler triple therapy (ICS/LAMA/LABA) significantly reduced the rate of moderate-to-severe exacerbations by approximately 15%. This suggests that for patients who continue to exacerbating on dual therapy, the addition of an ICS provides superior protection against further events.

Fellow

How do the results of the TRIBUTE trial complement or contrast with the findings of the FLAME trial regarding the role of ICS in COPD management?

Key Response

The FLAME trial established that LAMA/LABA was superior to LABA/ICS in preventing exacerbations. TRIBUTE takes this further by showing that triple therapy (ICS/LAMA/LABA) is superior to LAMA/LABA. Collectively, these trials suggest that while LAMA/LABA is a preferred backbone over LABA/ICS, the addition of an ICS to a dual bronchodilator regimen provides incremental benefit for high-risk exacerbators.

Attending

In light of the TRIBUTE findings, how should a clinician balance the 15% reduction in exacerbations with the known risk of pneumonia associated with long-term ICS use in COPD?

Key Response

The TRIBUTE study did not show a statistically significant increase in pneumonia between triple and dual therapy groups over 52 weeks, but the risk remains a class effect of ICS. Clinicians should use blood eosinophil counts (typically ≥300 cells/uL) and a history of multiple exacerbations or hospitalizations as biomarkers to identify patients where the benefit of exacerbation reduction outweigh the potential infectious risks.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The TRIBUTE trial used a randomized, parallel-group design with a 2-week run-in period on the patient's existing medication. How might this run-in design influence the 'withdrawal effect' and potentially bias the exacerbation rates observed in the dual therapy arm?

Key Response

If patients were previously on ICS-containing regimens and were randomized to the LAMA/LABA arm (IND/GLY), they underwent an abrupt ICS withdrawal. This can lead to a transient increase in airway inflammation and exacerbation risk in the control group, potentially overestimating the relative efficacy of the triple therapy arm which continued or initiated ICS.

Journal Editor

The primary endpoint of TRIBUTE was the rate of moderate-to-severe COPD exacerbations. Why is the choice of 'moderate' exacerbations (requiring antibiotics/corticosteroids) as a primary outcome often criticized in COPD trials, and how does it affect the trial's impact?

Key Response

Moderate exacerbations are partially defined by physician behavior (the decision to prescribe) rather than purely objective physiological changes. While TRIBUTE showed a statistically significant reduction in the total rate, editors look for consistency across secondary endpoints like severe exacerbations (hospitalizations) and lung function (FEV1) to ensure the primary finding isn't driven by subjective healthcare utilization patterns.

Guideline Committee

How does the TRIBUTE trial support the current GOLD 2024 recommendations for the transition from 'Group E' initial treatment to subsequent maintenance therapy?

Key Response

GOLD 2024 recommends LAMA/LABA as the preferred initial therapy for Group E (exacerbators), but suggests triple therapy is preferred if eosinophils are ≥300. TRIBUTE provides the 'Level A' evidence required to support the escalation to triple therapy for patients who continue to experience exacerbations on dual bronchodilation, reinforcing that triple therapy is the most effective pharmacologic intervention for preventing recurrences in this phenotype.

Clinical Landscape

Noteworthy Related Trials

2016

FLAME Trial

n = 3,362 · NEJM

Tested

Indacaterol and glycopyrronium (dual bronchodilator)

Population

Patients with COPD and history of exacerbations

Comparator

Salmeterol and fluticasone (ICS/LABA)

Endpoint

Time to first exacerbation

Key result: Dual bronchodilator therapy was superior to ICS/LABA in preventing COPD exacerbations.

2017

TRINITY Trial

n = 2,691 · Lancet Respir Med

Tested

Fixed-dose extrafine triple therapy (beclometasone, formoterol, and glycopyrronium)

Population

Patients with symptomatic COPD and history of moderate or severe exacerbations

Comparator

Tiotropium or fixed-dose combination of beclometasone and formoterol

Endpoint

Rate of moderate to severe exacerbations

Key result: The triple therapy significantly reduced the rate of moderate to severe exacerbations compared to the dual therapy and tiotropium arms.

2018

IMPACT Trial

n = 10,355 · NEJM

Tested

Fluticasone furoate, umeclidinium, and vilanterol

Population

Patients with symptomatic COPD and history of exacerbations

Comparator

Fluticasone furoate/vilanterol or umeclidinium/vilanterol

Endpoint

Annual rate of moderate to severe exacerbations

Key result: Triple therapy resulted in a lower annual rate of exacerbations compared to both dual therapies.

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