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Singh D, et al. "Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial". The Lancet. 2016. 388(10048):963-973.

Clinical Question

In patients with chronic obstructive pulmonary disease, is single inhaler triple therapy with beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide a safer and more effective treatment compared to beclometasone dipropionate and formoterol fumarate?

Bottom Line

Patients with severe COPD that are at risk for exacerbations will receive greater benefits from triple therapy with BDP/FF/GB than BDP/FF. The triple therapy as a single inhaler provides greater bronchodilation and helps prevent moderate-to-severe exacerbations, as well as improves patients’ quality of life.

Major Points

Per GOLD, long-acting muscarinic antagonists or inhaled corticosteroids plus long-acting β2 agonists are the initial choices for treatment, but can be stepped up to triple therapy if needed. Currently triple therapy includes two inhalers, one being a combination of an inhaled corticosteroid plus a β2 agonist, and the other a long-acting muscarinic antagonist. A single inhaler consisting of all three medications (BDP/FF/GB) has now been developed to simplify the current regimen.

The focus of the TRILOGY study was to compare the safety and efficacy of triple therapy with BDP/FF/GB to BDP/FF for patients with COPD at risk for exacerbations. BDP/FF/GB was found to be superior regarding both pre-dose FEV1 and 2-hour post-dose FEV1 at all visits compared to BDP/FF.

Increases in TDI (transition dyspnea index) focal scores from baseline , as well as improvements in SGRQ total score from baseline (decrease ≥4 units) were seen with BDP/FF/GB compared to BDP/FF.

Rescue inhaler use, as well as the frequency of moderate-to-severe exacerbations, were significantly lower with BDP/FF/GB. The time to exacerbations was also significantly prolonged compared to BDP/FF.

Based on the TRILOGY study, triple therapy was more effective in patients with symptomatic severe COPD at risk for exacerbations. Overall, BDP/FF/GB showed an improvement in breathing difficulties in patients. This treatment also led to fewer exacerbations, greater bronchodilation, and overall improved quality of life.


  • Gold guidelines (the Global Initiative for Chronic Obstructive Lung Disease)
    • For these patients: first choice long-acting muscarinic antagonist or an inhaled corticosteroid + long-acting β2 agonist
    • If still experiencing symptoms, can step up to triple therapy with all three medications


  • Randomized, parallel group, double-blind, active-controlled study
  • N=1368
    • BDP/FF: 681
    • BDP/FF/GB: 687
  • Setting: 159 sites across 14 countries
  • Mixture of primary (n=18), secondary (n=99), and tertiary (n=28) care providers, and specialist investigation units (n=14)
  • Enrollment: March 21, 2014- January 14, 2016
  • Analysis: Co-primary endpoints assessed with linear mixed model for repeated measures, including all data up to discontinuation. Secondary and exploratory endpoints were analyzed with a similar mixed model to that used for the primary outcomes. All outcomes were analyzed in the intention to treat population.
  • Primary Outcomes: Change from baseline in predose FEV1 , change from baseline in 2 hour post-dose FEV1, and TDI focal score


Inclusion Criteria

  • 40+ years of age
  • Diagnosis of COPD, with a post-bronchodilator FEV1 of less than 50% and a ratio of FEV1/FVC of less than 0.7
  • ≥1 moderate or severe COPD exacerbation in the previous 12 months
  • Use of an inhaled corticosteroid plus a long-acting β2 agonist (free or fixed combination), or an inhaled corticosteroid plus a long-acting muscarinic antagonist (free or fixed combination), or a long-acting β2 agonist plus a long-acting muscarinic antagonist (free or fixed combination), or a long acting muscarinic antagonist monotherapy for at least 2 months before screening
  • Symptomatic with a COPD assessment test (CAT) total score of 10 or more and a Baseline Dyspnea Index (BDI) focal score of 10 or less at screening with the BDI criterion also confirmed at the randomisation visit

Exclusion Criteria

  • Not eligible if receiving triple therapy of an inhaled corticosteroid plus a long-acting β2 agonist plus a long-acting muscarinic antagonist
  • Diagnosis of asthma or history of allergic rhinitis or atopy
  • COPD exacerbation in the 4 weeks before screening or during the run-in period
  • Clinically significant cardiovascular conditions or laboratory abnormalities
  • Unstable concurrent disease that might have affected efficacy or safety

Baseline Characteristics

Presented in order of BDP/FF/GB, BDP/FF

  • Male: 509, 527/ Female: 178, 153
  • White: 684, 679/ Other race: 3, 1
  • Mean age: 63.3, 63.8
  • BMI: 26.3, 26.4
  • Blood leucocyte concentration (109/L): 8.02, 8.13
  • Blood eosinophil concentration (109/L): 0.25, 0.24
  • Blood eosinophil proportion (%): 3.12, 3.06
  • Current smoker: 323, 318/ Ex-smoker: 364, 362
  • Time since first COPD diagnosis (years): 7.7, 7.7
  • FEV1 (L): 1.11, 1.10
  • FEV1 percentage predicted: 36.9, 36.2
    • 30%-50%: 532, 525
    • <30%: 155, 155
  • FVC (L): 2.73, 2.75
  • FEV1/FVC ratio: 0.42, 0.41
  • Reversibility: 10.4, 10.4
  • Chronic bronchitis: 450, 463
  • Exacerbation rate in the previous year: 1.2, 1.2
  • CAT total score: 20.8, 20.8
  • COPD medication at study entry:
    • ICS/LABA: 506, 487
    • ICS/LAMA: 10,10
    • LABA/LAMA: 95, 107
    • LAMA: 76, 76
  • Spacer used during study: 111, 129
  • Patients with at least 1 concomitant disease: 590, 563
  • HTN: 404, 382
  • IHD: 172, 173
  • DM: 90,89
  • Cardiac failure: 73, 86
  • Hypercholesterolemia: 45, 41
  • Respiratory failure: 35, 45
  • Gastritis: 36, 30
  • BPH: 24, 42
  • Cor pulmonale: 39, 25


  • All patients had initial 2-week run-in period
  • They received BDP (100μg) /FF (6μg) two actuations twice daily for 2 weeks
  • Randomization:
    • After run-in period, randomly assigned (1:1) and stratified by country and severity of airflow limitation
      • BDP (100μg) /FF (6μg) two actuations twice daily
      • BDP (100μg) /FF (6μg)/ GB (12.5μg) two actuations twice daily


Primary Outcomes

Change from baseline in pre-dose FEV1
baseline: 1.096
week 26: + 0.082 (1.178)
week 52: + 0.071 (1.249)
baseline: 1.094
week 26: + 0.001 (1.095)
week 52: + 0.008 (1.103)
Change from baseline in 2 hour post-dose FEV1
week 26: 0.261
week 52: 0.249
week 26: 0.145
week 52: 0.146
TDI focal score
week 26: 1.71
week 52: 2.03
week 26: 1.50
week 52: 1.81

Secondary Outcomes

Patients with FEV1 response (change from baseline in pre-dose FEV1 ≥100 mL) at weeks 26 and 52
week 26: 287
week 52: 259
week 26: 165
week 52: 158
Patients with change in TDI at weeks 26 and 52 (focal score of one or more minimum clinically important difference)
week 26: 394
week 52: 370
week 26: 352
week 52: 354
Patients with SGRQ response at weeks 26 and 52 (decrease in baseline ≥4 minimum clinically important difference)
week 26: 321
week 52: 297
week 26: 246
week 52: 244
Moderate to severe COPD exacerbation frequency over 52 weeks of treatment
BDP/FF/GB: 31%, BDP/FF: 35%,
Significant reduction in rate of 23% with BDP/FF/GB
Time to first moderate-to-severe COPD exacerbation
hazard ratio 0.80, 95% CI (0.67-0.97), p=0.020

Adverse Events

Presented in order of BDP/FF/GB, BDP/FF

  • There were similar proportion of events in both groups, with most being mild or moderate
  • Treatment emergent adverse events: 368, 379
  • COPD: 214, 240
  • Nasopharyngitis: 39, 38
  • Pneumonia: 23, 18
  • HTN: 21,16
  • Headache: 12, 16
  • IHD: 10,16
  • Respiratory tract infection viral: 16, 10
  • Oral candidosis: 15, 4
  • Serious treatment emergent adverse events: 106, 123
  • COPD: 106, 123
  • Pneumonia: 15, 7
  • IHD: 2, 11
  • Cardiac failure: 5, 5
  • Treatment related adverse events: 26, 14
  • Oral candidosis: 10, 2
  • Muscle spasms: 5, 3
  • Dry mouth: 4, 2
  • Serious treatment related adverse events: 1, 0
  • Severe treatment emergent adverse events: 77, 86
  • Treatment emergent adverse events leading to study drug discontinuation: 35, 33
  • Treatment emergent adverse events leading to death: 15, 16
  • Major adverse cardiovascular events: 15, 15


  • Issues with measuring TDI included the need for patients to recall previous symptoms. This recall bias could be an issue in longer studies and could affect this outcome.
  • The study did not evaluate escalation to triple therapy from a long-acting β2 agonist in combination with a long-acting muscarinic antagonist. Therefore the benefit of adding on an inhaled corticosteroid to create triple therapy cannot be established. Treatment with triple therapy versus a combination of a long-acting β2 agonist plus a long-acting muscarinic antagonist can also not be compared to determine efficacy.
  • A run-in period was used to establish all patients on the same initial treatment with an inhaled corticosteroid and long acting β2 agonist. However, a longer run-in period may have eliminated some possible trial effect on patient-reported outcomes.
  • Due to the variety of available inhaler devices, this could present a challenge in simplifying therapy to a single inhaler for triple therapy. Because certain devices are more difficult to use properly, this could be a problem for certain patient populations, such as elderly. Some inhalers may be confusing to manipulate or physically difficult to use. When simplifying the regimen to a single inhaler, a device that is easier to use should be considered, such as an MDI.


  • Those funding the study were responsible for the design and analysis. Funders also oversaw the conduct and prepared the study report.

Further Reading