Efficacy and Safety of Gly/Form/Bud Triple Therapy versus Dual Therapy in COPD

27 Jan, 21

Introduction

Triple therapy with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ?₂-agonist (LABA) has been associated with a lower risk of chronic obstructive pulmonary disease (COPD) exacerbations, a greater reduction in symptoms, and better lung function and health-related quality of life as compared to dual therapies. Triple therapy is beneficial in patients who continue to have symptoms or exacerbations while receiving dual therapy with LAMA–LABA or inhaled glucocorticoid–LABA. Triple fixed-dose regimens have been studied at single dose levels of inhaled glucocorticoid. However, there is paucity of data at two dose levels.

Aim

This 52-week trial compares the efficacy and safety of two single-inhaler, triple fixed-dose combinations (i.e., budesonide at two different doses plus a LAMA and a LABA) with those of two dual therapies (LAMA–LABA and inhaled glucocorticoid–LABA).

Patient Profile

Age 40 to 80 years with symptomatic COPD (defined as a score of ≥10 on the COPD Assessment Test)
Subjects were receiving at least two inhaled maintenance therapies at the time of screening
Had a postbronchodilator ratio of the forced expiratory volume in 1 second (FEV₁) to the forced vital capacity (FVC) of less than 0.7
A postbronchodilator FEV₁ of 25 to 65% of the predicted normal value
Smoking history of at least 10 pack-years
History of at least one moderate or severe COPD exacerbation (if their FEV₁ was <50% of the predicted normal value) or at least two moderate or at least one severe COPD exacerbation (if their FEV₁ was ≥50% of the predicted normal value) in the year before screening

Method

Study Design

Randomized, double-blind, parallel-group, 52-week, phase 3 trial conducted in 26 countries

Treatment Strategy

The cohort was randomized in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 ?g or 160 ?g of budesonide], a LAMA [18 ?g of glycopyrrolate], and a LABA [9.6 ?g of formoterol]) or one of two dual therapies (18 ?g of glycopyrrolate plus 9.6 ?g of formoterol or 320 ?g of budesonide plus 9.6 ?g of formoterol).
Randomization was stratified according to exacerbation history (1 or ≥2 moderate or severe exacerbations), postbronchodilator FEV₁ (25 to <50% or 50 to <65% of the predicted normal value), blood eosinophil count (<150 or ≥150 cells per cubic millimeter), and country.

End Points

Primary End Point

Annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population

Secondary End Points

Time to the first moderate or severe COPD exacerbation
Annual rate of severe COPD exacerbations
Time to death from any cause
Change from baseline in average daily use of rescue medication over 24 weeks
Percentage of patients who had a St. George’s Respiratory Questionnaire (SGRQ) response
Adverse events (AEs)

Results

The safety population included 8529 patients, and the intention-to-treat and modified intention-to-treat populations comprised 8509 patients.
The annual rates of moderate or severe exacerbations are shown in Table 1.
- The 320-?g–budesonide triple therapy had a 24% lower rate of exacerbations as compared to the glycopyrrolate–formoterol (rate ratio, 0.76; p<0.001) and 13% lower rate than the budesonide–formoterol (rate ratio, 0.87; p=0.003).
- The 160-?g–budesonide triple therapy also demonstrated a 25% lower rate and 14% lower rate than with glycopyrrolate–formoterol and budesonide–formoterol groups respectively (rate ratio, 0.75; p<0.001 and rate ratio, 0.86; p=0.002 respectively).
Both triple-therapy regimens significantly prolonged the time to the first moderate or severe exacerbation as compared with both dual therapies. (Table 1)
- The 320-?g–budesonide triple therapy had a 12% lower risk compared to glycopyrrolate–formoterol (p=0.004) and 11% lower risk than the budesonide–formoterol (p=0.006).
The risk of death from any cause in the 320-?g–budesonide triple-therapy group was 46% lower than that in the glycopyrrolate–formoterol group (28 vs. 49 deaths; hazard ratio, 0.54) and 22% lower than that in the budesonide–formoterol group (28 vs. 34 deaths; hazard ratio, 0.78) (Table 1).
The risk of death from any cause in the 160-?g–budesonide triple-therapy group was lower than that in the glycopyrrolate–formoterol group (39 vs. 49 deaths; hazard ratio, 0.79) but higher than that in the budesonide–formoterol group (39 vs. 34 deaths; hazard ratio, 1.13) (Table 1). The comparisons also showed favourable trends for 320-?g–budesonide triple therapy with respect to severe exacerbations, SGRQ response, and use of rescue medication (Table 1).

Table 1. Efficacy endpoints

	320-?g–budesonide triple-therapy group (n=2137)	160-?g–budesonide triple-therapy (n=2121)	Glycopyrrolate-formoterol group (n=2120)	Budesonide-formoterol group (n=2131)
Primary endpoint
Primary analysis: Annual rate of moderate or severe COPD exacerbations	1.08	1.07	1.42	1.24

Secondary endpoints
Time to first moderate or severe COPD exacerbations over 52 weeks (% of patients with exacerbations)	48%	47.8%	49.8%	50.9%
Annual rate of severe exacerbations	0.13	0.14	0.15	0.16
Rate ratio: 320-?g–budesonide triple therapy vs. comparators		0.96	0.84 (p=0.09)	0.80 (p=0.02)
Time to death from any cause over 52 weeks (% of patient deaths)	1.3%	1.8%	2.3%	1.6%
Percentage of patients achieving a decrease of ≥ 4 units in SGRQ total score at Week 52: Responders (%)	44.2%	43.1%	36.5%	39.2%
Change from baseline in average daily rescue medication use over 24 weeks (Mean)	-1.2	-1.0	-0.7	-0.8
Mean: 320-?g–budesonide triple therapy vs. comparators		-0.15	-0.51	-0.37

The incidence of any AE was comparable across the treatment groups and ranged from 61.7% to 64.5%
The incidence of pneumonia was 4.2% and 3.5% in the 320 ?g and 160 ?g –budesonide triple-therapy groups respectively and 2.3% and 4.5% in the glycopyrrolate–formoterol and budesonide-formoterol groups respectively.

Conclusions

Triple therapy with budesonide, glycopyrrolate, and formoterol was associated with a lower rate of moderate or severe COPD exacerbations and better health-related quality of life than dual therapy with glycopyrrolate–formoterol or budesonide–formoterol.

N Engl J Med. 2020 Jul 2;383(1):35-48. Doi: 10.1056/NEJMoa1916046.