Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD

Incomplete

Wedzicha JA, et al. "Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD". New England Journal of Medicine. 2016. 374(23):2222-2234.
PubMed • Full text

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Clinical Question

In patients with moderate to severe chronic obstructive pulmonary disease, is the combination of a long-acting beta-agonist and a long-acting muscarinic antagonist safe and more effective than a long-acting beta-agonist plus a corticosteroid at preventing exacerbations?

Bottom Line

In patients with moderate or severe COPD, Indacaterol–glycopyrronium was more effective than salmeterol–fluticasone in preventing COPD exacerbations and was not associated with an increase in adverse events.

Major Points

Exacerbations of COPD are associated with decreased quality of life¹, damaged lung function², and overall increased mortality³. Prevention of exacerbations is a major goal in managing COPD⁴. To treat moderate to severe COPD exacerbations, most guidelines recommend either a long-acting beta-agonist (LABA) with inhaled corticosteroid (ICS) or a long-acting muscarinic antagonist (LAMA) alone. While the role of treatment with a LABA-ICS was defined in the guidelines, the combination therapy of LABA-LAMA remains unclear. In the FLAME trial (2016), a regimen including a LABA-LAMA was studied alongside a regimen including a LABA-ICS to determine which treatment would be the most safe and effective to decrease COPD exacerbations in patients

The FLAME trial was a 52 week trial that took 3362 patients with a history of COPD exacerbation and randomized them into two treatment groups: indacaterol-glycopyrronium (LABA-LAMA) and salmeterol-fluticasone (LABA-ICS). After 52 weeks indacaterol-glycopyrronium showed an 11% lower rate of COPD exacerbations and a longer time to the first exacerbation (71 days vs 51 days). All severities of exacerbations were assessed (mild, moderate, severe) and resulted in consistent benefit towards using LABA-LAMA treatment for prevention. There was a difference in the adverse event pneumonia (incidence 3.2% vs 4.8%; p=.02; NNT 63) in favor of LABA-LAMA.

A patient journal was used to assess results of the trial for all severities of exacerbations, most common being mild. This had potential to skew results in favor of LABA-LAMA treatment because mild exacerbations are not normally studied and recorded, but the moderate-severe exacerbations showed similar decrease in exacerbations. Also, patients who were previously treated long-term with LABA-ICS prior to enrollment and then placed on LABA-LAMA treatment had potential withdrawal effects from the ICS that could have resulted in more exacerbations.

Guidelines

Global Initiative for Chronic Obstructive Lung Disease (GOLD, 2017)⁴

Bronchodilators (beta-agonists, anticholinergics, methylxanthines) are central to the symptomatic management of COPD
Regular treatment with long-acting bronchodilators is more effective and convenient than treatment with short-acting bronchodilators.
Glucocorticosteroids plus bronchodilators are an appropriate treatment for symptomatic patients with stage 3 and 4 (severe-very severe) and with repeated exacerbations.

National Institute for Health and Care Excellence (NICE, 2010)⁵

Offer once-daily long-acting muscarinic antagonist (LAMA) in preference to four-times-daily short-acting muscarinic antagonist (SAMA) to people with stable COPD who remain breathless or have exacerbations despite using short-acting bronchodilators as required, and in whom a decision has been made to commence regular maintenance bronchodilator therapy with a muscarinic antagonist.

In people with stable COPD who remain breathless or have exacerbations despite using short-acting bronchodilators as required, offer the following as maintenance therapy:
- if FEV₁ ≥ 50% predicted: either long-acting beta2 agonist (LABA) or LAMA
- if FEV₁ < 50% predicted: either LABA with an inhaled corticosteroid (ICS) in a combination inhaler, or LAMA

In people with stable COPD and an FEV₁ ≥ 50% who remain breathless or have exacerbations despite maintenance therapy with a LABA:
- consider LABA+ICS in a combination inhaler
- consider LAMA in addition to LABA where ICS is declined or not tolerated.

Offer LAMA in addition to LABA+ICS to people with COPD who remain breathless or have exacerbations despite taking LABA+ICS, irrespective of their FEV₁.
Consider LABA+ICS in a combination inhaler in addition to LAMA for people with stable COPD who remain breathless or have exacerbations despite maintenance therapy with LAMA irrespective of their FEV₁.

Design

Randomized, double-blind, double-dummy, noninferiority trial
N=3362
- Indacaterol–glycopyrronium group (n=1680)
- Salmeterol–fluticasone group (n=1682)
Setting: 43 countries around the world
Enrollment: July 2013-September 2015
Duration: 52 weeks with 30 day post follow up
Analysis: Per-protocol, modified intention-to-treat
- modified intention-to-treat population included all patients who underwent randomization, received at least one dose of a drug during the treatment period, and did not have major violations of compliance with Good Clinical Practice guidelines before un-blinding occurred
Primary outcome: the annual rate of all COPD exacerbations (mild, moderate, or severe)

Population

Inclusion Criteria

Age ≥40 years that were current or previous smokers with a smoking history of ≥ 10 pack-years
Stable COPD according to the GOLD 2011 criteria on stable medication therapy for at least 60 days prior to screening period
Patients with a post-bronchodilator FEV₁ 25-60% of the predicted normal value and post-bronchodilator FEV₁ <0.70 one hour after sequential administration of 84 µg of ipratropium bromide and 400 µg of salbutamol
At least 1 COPD exacerbation in the previous 12 months treated with systemic corticosteroids and/or antibiotics
Patients with a modified Medical Research Council (mMRC) grade ≥2 at the start of the run-in period

Exclusion Criteria

Pregnant or nursing (lactating) women, or women of childbearing age not on contraception
Patients with Type I or uncontrolled Type II diabetes.
Patients with a history of long QT syndrome or whose QTc measured >450ms
Patients with an EKG abnormality
Patients who had clinically significant renal, cardiovascular, arrhythmia, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities
Patients with paroxysmal (e.g. intermittent) atrial fibrillation
Patients contraindicated for treatment with, or having a history of reactions/ hypersensitivity to any excipients of trial drugs
Patients with a history of malignancy of any organ system, treated or untreated, within the past 5 years
Patients with narrow-angle glaucoma, symptomatic benign prostatic hyperplasia or bladder-neck obstruction or moderate-to-severe renal impairment or urinary 10 retention
Patients who had not achieved an acceptable spirometry result at the start of the run-in period
Patients who had a COPD exacerbation that resulted in treatment with antibiotics and/or systemic corticosteroids and/or hospitalization in the 6 weeks prior to Visit 1
Patients who developed a respiratory tract infection 4 weeks prior to screening, between screening or prior to treatment
Patients requiring long-term oxygen therapy prescribed for >12 hours per day
Patients with any history of asthma
Patients with an onset of respiratory symptoms, including a COPD diagnosis prior to age 40 years
Patients with a blood eosinophil count >600/mm3 at the start of the run-in period (Visit 101)
Patients with concomitant pulmonary disease o Patients with clinically significant bronchiectasis
Patients with a diagnosis of α-1 anti-trypsin deficiency. o Patients with active pulmonary tuberculosis
Patients with pulmonary lobectomy or lung volume reduction surgery or lung transplantation
Patients receiving selective serotonin reuptake inhibitors, intra-nasal corticosteroids, H1-antagonists, or inactivated influenza, pneumococcal or any other inactivated vaccine, were excluded unless the medication had been stable for the specified period and the stated conditions had been met
Use of other investigational drugs/devices (approved or unapproved) at the time of enrollment

Baseline Characteristics

For All Patients in Study

40 years of age or older (mean:65), male (76%)
COPD duration: 7 years
iCS use at screening: 56%
Current smoker: 40%
Severity of COPD:
- Group A: low risk, low symptom (< 1%)
- Group B: low risk, high symptom (24%)
- Group C: high risk, low symptom (< 1%)
- Group D: high risk, high symptom (75%)

a post-bronchodilator FEV₁: 1.2 L
FEV₁ % predicted value: 44%
ratio of FEV₁ to forced vital capacity (FVC): 42%
Total score on SGRQ-C: 47 (scores range 0-100, with increasing score indicating worsening health)

Interventions

Participants underwent 1 week screening period and then treated with tiotropium 18 μg/day inhalation for 4 weeks
Discontinued tiotropium and randomly assigned to two treatment groups for 52 weeks
- indacaterol 110 μg plus glycopyrronium 50 μg once daily inhalations
- salmeterol 50 μg plus fluticasone 500 μg twice daily inhalations
Salbutamol 100 μg was provided as rescue medication

Outcomes

Presented as Indacaterol–Glycopyrronium vs. Salmeterol–Fluticasone

Primary Outcome

Rate of COPD Exacerbations

3.59 vs. 4.09 (RR 0.88; 95% CI 0.82-0.94; p<0.001)

Secondary Outcomes

Time to First Exacerbation

71 vs. 51 days (HR 0.84; 95% CI 0.78-0.91; p<0.001)

Time to First Moderate-Severe Exacerbation

127 vs. 87 days (HR 0.78; 95% CI 0.70-0.86, p<0.001)

Time to First Severe Exacerbation

(HR 0.81; 95% CI 0.66-1.00; P = 0.046)

Annual Rate of Moderate-Severe exacerbation

0.98 vs. 1.19 (RR 0.83; 95% CI 0.75-0.91; p<0.001)

Annual Rate of Severe Exacerbation

0.15 vs. 0.17 (RR 0.87; 95% CI 0.69-1.09; p = 0.23)

Difference in change of FEV1 from baseline to week 52

Difference between two groups= 62 mL, favoring I-G; P<0.001

Clinically Important Decrease on SGRQ-C of at least 4 points

49.2% vs. 43.7% (OR=1.30; p<0.001) NNT=18

Decrease in Mean Daily Puffs of Rescue Medication From Baseline

1.01 vs. 0.76 puff/day (P<0.001)

Subgroup Analysis

There were a few statistically significant differences in the rate of primary outcomes when analyzed by sex, race, smoking status, severity of airflow limitation, severity of COPD, and previous year COPD exacerbations; however, these were not clinically significant when examining NNTs.<br>

Adverse Events

Incidence of Pneumonia

3.2% vs 4.8% (p=0.02) NNT=63

Most adverse event rates were comparable between the two groups; however, worsening of COPD, Bacterial URI, Influenza, oral candiasis, and serious adverse event rates appeared to be different between the two groups, but p-values were not provided on these differences.

Criticisms

The same company funding the study helped verify the key results.
Novartis is the company that manufactured the Breezhaler (therapy that showed better results in the trial)
Aside from pneumonia, they did not assess any other significant adverse events statistically

Funding

The study was funded by Novartis who also helped develop the protocol, performed trial monitoring and reporting, provided oversight, verified key results provided by DataMap and also manufactures the Breezhaler (which showed better results in the trial).

Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD

Contents

Clinical Question

Bottom Line

Major Points

Guidelines

Design

Population

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Interventions

Outcomes

Primary Outcome

Secondary Outcomes

Subgroup Analysis

Adverse Events

Criticisms

Funding

Further Reading

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Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD

Clinical Question

Bottom Line

Major Points

Guidelines

Design

Population

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Interventions

Outcomes

Primary Outcome

Secondary Outcomes

Subgroup Analysis

Adverse Events

Criticisms

Funding

Further Reading

Navigation menu

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