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

Alberto Papi, Jørgen Vestbo, Leonardo Fabbri, et al.

Bottom Line

In patients with severe, symptomatic COPD and a history of exacerbations, a single-inhaler extrafine triple therapy (ICS/LABA/LAMA) significantly reduced the rate of moderate-to-severe exacerbations compared to dual bronchodilator therapy (LABA/LAMA) over 52 weeks, without increasing pneumonia risk.

Key Findings

1. Treatment with extrafine triple therapy (BDP/FF/G) resulted in a 15% reduction in the rate of moderate-to-severe COPD exacerbations compared to dual bronchodilator therapy (IND/GLY), with annual rates of 0.50 vs 0.59 per patient, respectively (Rate Ratio [RR] 0.848, 95% CI 0.723-0.995; p=0.043).

2. The overall incidence of adverse events was similar between the two groups, occurring in 64% (490/764) of patients receiving BDP/FF/G and 67% (516/768) of patients receiving IND/GLY.

3. Unlike several prior studies involving inhaled corticosteroids, the risk of pneumonia was not significantly increased with triple therapy, occurring in 4% (28 patients) in the BDP/FF/G arm versus 4% (27 patients) in the IND/GLY 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 (FEV1 < 50% predicted), and at least one moderate or severe exacerbation in the previous year, who were receiving inhaled maintenance medication.

Intervention Single-inhaler extrafine triple therapy with beclometasone dipropionate 87 μg, formoterol fumarate 5 μg, and glycopyrronium 9 μg (BDP/FF/G), administered as two inhalations twice per day.

Comparator Single-inhaler dual bronchodilator therapy with indacaterol 85 μg plus glycopyrronium 43 μg (IND/GLY), administered as one inhalation per day.

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

Study Limitations

• Prior to randomization, patients discontinued their previous inhaled maintenance medications (including inhaled corticosteroids) and underwent a 2-week run-in on IND/GLY; abrupt withdrawal of ICS in the control arm may have precipitated rebound exacerbations, potentially exaggerating the benefit of triple therapy.

• The 52-week duration, while standard for exacerbation trials, is relatively short for assessing long-term systemic side effects of inhaled corticosteroids (e.g., bone mineral density loss, cataracts).

• The exclusion of patients with a history of concurrent asthma (only 1 reported in the trial) means findings may not strictly generalize to the asthma-COPD overlap phenotype, though it isolates the pure COPD effect.

Clinical Significance

The TRIBUTE trial provided critical head-to-head evidence supporting the step-up to triple therapy (ICS/LABA/LAMA) from dual bronchodilation (LABA/LAMA) for COPD patients who continue to experience exacerbations despite maintenance therapy. The fact that the triple combination achieved a statistically significant reduction in exacerbations without increasing the incidence of pneumonia offered a favorable risk-benefit profile, cementing single-inhaler triple therapy as a foundational recommendation in GOLD guidelines for this specific, high-risk patient subgroup.

Historical Context

Prior to TRIBUTE, the management of severe COPD historically relied on stepping up from monotherapy to either ICS/LABA or LABA/LAMA combinations. Observational data and earlier trials suggested triple therapy (administered via multiple inhalers) improved lung function and symptoms, but rigorous randomized data demonstrating superiority in exacerbation reduction against the highly effective LABA/LAMA dual class were scarce. Published alongside the landmark IMPACT trial in 2018, TRIBUTE firmly established the clinical superiority of single-inhaler triple therapy over dual bronchodilators for exacerbation-prone patients.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the distinct mechanisms of action of the three classes of medications (ICS, LABA, LAMA) used in the TRIBUTE trial's triple therapy, and what is the pathophysiological rationale for using an inhaled corticosteroid specifically in a patient with a history of COPD exacerbations?

Key Response

LABAs stimulate beta-2 adrenergic receptors for bronchodilation, LAMAs block muscarinic receptors to prevent bronchoconstriction and reduce mucus hypersecretion, and ICS reduces airway inflammation. In COPD patients with frequent exacerbations, particularly those with eosinophilic inflammation, ICS reduces mucosal edema and inflammatory flares, preventing the acute worsening of symptoms.

Resident

Based on the TRIBUTE trial and current GOLD criteria, when should a clinician step up a COPD patient from a LABA/LAMA combination to triple therapy (ICS/LABA/LAMA), and what clinical biomarker helps predict the benefit of adding the ICS?

Key Response

Triple therapy is indicated for patients who continue to have frequent exacerbations (>=2 moderate or >=1 leading to hospitalization per year) despite dual bronchodilator therapy. The blood eosinophil count is the key biomarker; counts >= 100 cells/mcL, and especially >= 300 cells/mcL, predict a strong response to the addition of an ICS in reducing future exacerbations.

Fellow

The TRIBUTE trial reported no increased risk of pneumonia with the ICS-containing triple therapy compared to LABA/LAMA, which contrasts with older trials like TORCH. How might the formulation and specific choice of corticosteroid explain this discrepancy?

Key Response

TRIBUTE utilized an extrafine particle formulation of beclometasone. Extrafine particles achieve higher peripheral lung deposition with less oropharyngeal and central airway impaction. Additionally, beclometasone has different pharmacokinetic properties and is generally associated with a lower risk of local immunosuppression and pneumonia in COPD compared to fluticasone, which was the ICS used in TORCH.

Attending

The TRIBUTE trial demonstrated a 15 percent reduction in moderate-to-severe exacerbations using a single-inhaler triple therapy. From a real-world practice perspective, how does the delivery method of a single inhaler versus multiple concurrent inhalers influence long-term COPD outcomes?

Key Response

A major barrier in COPD management is poor inhaler technique and non-adherence due to complex polypharmacy. Single-inhaler regimens reduce the number of devices a patient must master, significantly improving adherence and decreasing critical handling errors. This translates the clinical efficacy seen in trials into actual real-world effectiveness, reducing hospitalizations in older, complex patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Patients in the TRIBUTE trial may have been on ICS before enrollment and were randomized after a run-in phase. How does the methodological phenomenon of 'ICS withdrawal' complicate the interpretation of exacerbation rates in the LABA/LAMA control arm?

Key Response

If patients previously stabilized on ICS are randomized to the LABA/LAMA arm, they undergo abrupt or recent ICS withdrawal. This withdrawal can transiently precipitate exacerbations in the control group, potentially inflating the apparent protective effect and exacerbation reduction attributed to the ICS-containing triple therapy arm.

Journal Editor

One methodological critique of the TRIBUTE trial is the choice of the active comparator. The triple therapy used beclometasone/formoterol/glycopyrronium, while the control arm used indacaterol/glycopyrronium. How does this mismatch in the LABA backbone threaten the construct validity of the study?

Key Response

Because the study did not use the exact same LABA/LAMA backbone in both arms, a stringent reviewer would argue that the observed 15 percent reduction in exacerbations cannot be solely attributed to the addition of the ICS (beclometasone). Differences in the intrinsic efficacy or duration of action between formoterol and indacaterol act as an unmeasured confounding variable.

Guideline Committee

How do the findings of the TRIBUTE trial, alongside evidence from IMPACT and ETHOS, inform the current GOLD guidelines regarding the positioning of ICS/LABA/LAMA triple therapy, and what specific parameters are now recommended to guide this step-up?

Key Response

These pivotal trials established the mortality and exacerbation benefits of triple therapy for high-risk patients. Current GOLD guidelines incorporate this by recommending triple therapy for Group E patients (high exacerbation risk) who remain symptomatic on LABA/LAMA, or as initial therapy if blood eosinophils are >= 300 cells/mcL. This shifted the paradigm from broad empirical ICS use to precision medicine guided by exacerbation history and eosinophil thresholds.

Clinical Landscape

Noteworthy Related Trials

2016

FLAME Trial

n = 3,362 · NEJM

Tested

Indacaterol/glycopyrronium (LAMA/LABA)

Population

COPD patients with a history of at least one exacerbation in the previous year

Comparator

Fluticasone/salmeterol (ICS/LABA)

Endpoint

Annual rate of all COPD exacerbations

Key result: LAMA/LABA dual therapy was superior to ICS/LABA in preventing COPD exacerbations.

2018

IMPACT Trial

n = 10,355 · NEJM

Tested

Fluticasone furoate/umeclidinium/vilanterol

Population

Symptomatic COPD patients with a history of exacerbations

Comparator

Fluticasone furoate/vilanterol (ICS/LABA) or Umeclidinium/vilanterol (LAMA/LABA)

Endpoint

Annual rate of moderate or severe COPD exacerbations

Key result: Single-inhaler triple therapy resulted in a significantly lower rate of moderate or severe COPD exacerbations than either dual therapy.

2020

ETHOS Trial

n = 8,509 · NEJM

Tested

Budesonide/glycopyrrolate/formoterol

Population

Patients with moderate-to-severe COPD and a history of exacerbations

Comparator

Glycopyrrolate/formoterol (LAMA/LABA) or Budesonide/formoterol (ICS/LABA)

Endpoint

Annual rate of moderate or severe COPD exacerbations

Key result: Triple therapy significantly reduced the rate of moderate or severe exacerbations compared with LAMA/LABA or ICS/LABA dual therapies.

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