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Lipson DA, et al. "Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD". New England Journal of Medicine. 2018. 378(18):1671-1680.
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Clinical Question

In patients with COPD, does once-daily single-inhaler triple therapy (inhaled glucocorticoid, LAMA, and LABA) decrease moderate or severe exacerbations vs once-daily single-inhaler dual therapy (either inhaled glucocorticoid-LABA or LABA-LAMA).

Bottom Line

Triple therapy resulted in a lower rate of moderate or severe COPD exacerbations than dual therapy in the population selected. Further, triple therapy resulted in lower hospitalization rate for moderate or severe COPD exacerbations. Lastly, there was higher incidence of pneumonia reported in the groups using inhaled glucocorticoids especially with triple therapy vs dual LAMA-LABA.

Major Points

Previous GOLD guidelines for COPD recommend initiating treatment with LAMA or LABA with step up therapy as needed for control. These guidelines recommend not starting inhaled corticosteroid until a patient is GOLD group D, with severe loss of lung function and/or frequent exacerbations. Evidence supporting the step up to triple therapy is lacking and the writers of GOLD guidelines even recommended further research on this topic. The IMPACT trial is the first study that looks at step up from dual bronchodilator therapy to triple therapy.




  • Multicenter, double-blind, parallel-group, randomized phase 3 trial
  • N=10,355
    • Triple Therapy (n=4,151)
    • Inhaled Corticosteroid-LABA (n=4,134)
    • LAMA-LABA (n=2,070)
  • Setting: Conducted in 37 countries between June 2014 through July 2017
  • Follow-up/Duration: 52 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: annual rate of moderate or severe COPD exacerbations


Inclusion Criteria

  • 40 years of age or greater
  • Symptomatic COPD by COPD Assessment Test score ≥ 10 (range 0 to 40 with higher score indicating more symptoms
  • FEV1 <50% of predicted normal value and at least one moderate or severe COPD exacerbation in the previous year, or
  • FEV1 50 to 80% of predicted normal value and at least two moderate exacerbations or one severe exacerbation within the previous year
  • Patient with Asthma were included if they also had a current diagnosis of COPD

Exclusion Criteria

  • Pregnant patients
  • Diagnosis of Asthma without COPD
  • α1-antitrypsin deficiency as the underlying cause of COPD
  • Active tuberculosis, lung cancer, significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases
  • Lung volume reduction surgery within the 12 months prior to selection
  • Those with risk factors for pneumonia such as being immunocompromised or having neuromuscular disorders that affect the upper airway
  • Abnormal chest x-ray that would hinder the ability to detect a new infiltrate
  • Untreated/Uncontrolled other medical problems including heart and liver disease.
  • Abnormal 12-lead ECG
  • Current Pneumonia or COPD exacerbation not resolved within the last 14 days prior to screen
  • Cancer
  • Oxygen therapy >3L/min
  • Pulmonary rehab within the 4 weeks prior to screening
  • Drug or alcohol abuse
  • Non-compliance

Baseline Characteristics

  • Mean age: 65.3 yrs
  • Female sex: 34%
  • Mean BMI: 26.6
  • Former Smokers: 65%
  • Moderate or Severe COPD Exacerbations in previous year
    • 0: <1%
    • 1: 45%
    • 2: 43%
    • ≥3: 11%
  • ≥2 Moderate COPD exacerbations in the previous year: 47%
  • ≥1 Severe COPD exacerbations in the previous year: 26%
  • ≥2 Severe COPD exacerbations in the previous year: 4%
  • Mean postbronchodilator FEV1 % of predicted normal value: 45.5
  • Mean score on the COPD assessment Test at screening: 20.1


  • Randomized to triple therapy (Fulticasone Furoate-Umeclidinium-Vilanterol), or double therapy (Fluticasone Furoate-Vilanterol or Umeclidinium-Vilanterol)
  • 2-week run-in period, 52-week treatment period, 1-week safety follow-up period
  • Outpatient clinic visits at pre-screening/screening, Randomization (Day 1), weeks 4, 16, 28, 40, 52 weeks of treatment with clinic visit or telephone call 7 days after discontinuing intervention
  • All treatments delivered by ELLIPTA™ dry powder inhaler (DPI)
  • Patients logged symptoms in an electronic diary every morning. If patients logged worsening symptoms suggestive of a COPD exacerbation over 2 days, investigators would be notified
  • Moderate Exacerbation defined by needing antibiotics or systemic corticosteroids
  • Severe Exacerbation defined by requiring hospitalization or resulting in death


Comparisons are triple therapy vs. dual therapy.

Primary Outcomes

Annual rate of moderate or severe COPD exacerbation during treatment
0.91 per year with FF-UMEC-VI group vs 1.07 with FF-VI group (rate ratio with triple therapy, 0.85; 95% CI, 0.80 to 0.90; 15% difference; P<0.001) vs 1.21 with UMEC-VI group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001)

Secondary Outcomes

Change from baseline trough FEV1 at Week 52
94mL FF-UMEC-VI group (95% CI, 86 to 102) vs -3mL FF-VI group (95% CI, -12 to 6) vs 40mL UMEC-VI group (95% CI, 28 to 52)
Change from baseline SGRQ Total Score at Week 52
-5.5 FF-UMEC-VI group (95% CI, -5.9 to -5.0) vs -3.7 FF-VI group (95% CI, -4.2 to -3.2) vs -3.7 UMEC-VI group (95% CI, -4.4 to -3.0)

Adverse Events

  • Pneumonia
  • Lower respiratory infections excluding pneumonia
  • Anticholinergic syndrome
  • Cardiac arrhythmia
  • Cardiac failure
  • Hypertension
  • Ischemic heart disease
  • Urinary Retention


40% of the patients enrolled in the trial were receiving treatment with triple therapy, more than 70% were receiving an inhaled glucocorticoid, and patient patients with a history of asthma were included. Therefore, many of the patients who were assigned to the LAMA-LABA group were actually stepping down in there treatment and had their inhaled glucocorticoid abruptly withdrawn at the start of the trial, likely leading to exacerbations. Data review notes a large surge of exacerbations in the LAMA-LABA group at the start of the trial, but similar rates of exacerbations in LAMA-LABA vs triple therapy groups over the subsequent months. This likely is overestimating the benefit of triple therapy vs LAMA-LABA comparator.


Funded by GlaxoSmithKline; Lead author is an employee of the sponsor.

Further Reading

Lipson, D. A., Barnhart, F., Brealey, N., Brooks, J., Criner, G. J., Day, N. C., … Pascoe, S. J. (2018). Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. New England Journal of Medicine, 37818378(3), NEJMoa1713901. [1] Trial Protocol[2]