Gly/Form/Bud Triple Therapy is Clinically Beneficial in Patients with Moderate to Very Severe COPD

10 Feb, 21

Introduction

Real-world evidence suggests that inhaled corticosteroids (ICS) have been used in patients with chronic obstructive pulmonary disease (COPD) as an open triple therapy with fixed-dose combination of ICS and a long-acting muscarinic antagonist (LAMA), and a long-acting ?₂-agonist (LABA). Studies comparing the efficacy of triple therapy with dual therapies such as LABA and LAMA or ICS and LABA across the spectrum of patients with COPD are scarce.

Aim

The efficacy of budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler (BGF MDI) has been compared with dual therapies such as glycopyrrolate/formoterol fumarate (GFF) MDI and budesonide/formoterol fumarate (BFF) MDI in symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.

Patient Profile

Current or former smokers (with a smoking history of ≥10 pack-years) aged between 40-80 years with a clinical diagnosis of COPD
Patients were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening

Method

Study Design

KRONOS - Randomized, double-blind, parallel-group, multicenter, phase 3 trial

Treatment Strategy

The study cohort was randomized 2:2:1:1 using an interactive web response system to receive BGF MDI 320/18/9·6 ?g (BGF MDI), GFF MDI 18/9·6 ?g, BFF MDI 320/9·6 ?g, or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 ?g (BUD/ FORM DPI).
The cohort received 2 inhalations twice-daily for 24 weeks
During each visit, spirometry was done and the St George’s Respiratory Questionnaire (SGRQ) was filled in by the subjects
At screening, the subjects filled in the Baseline Dyspnoea Index (BDI) questionnaire and the Transition Dyspnoea Index (TDI) questionnaire was completed at the remaining visits

End Points

Primary Endpoints

Forced expired volume in 1 second (FEV₁) area under the curve from 0-4 h (AUC_0-4) over 24 weeks (Europe and Canada) / at week 24 (USA)
Change from baseline in morning pre-dose trough FEV₁ over 24 weeks (Europe and Canada) / at week 24 (USA)

Secondary Endpoints

Rate of moderate or severe COPD exacerbations, TDI focal score, change from baseline in daily rescue medication use, change from baseline in SGRQ total score, E-RS: COPD total score (RS-Total score), and time to clinically important deterioration i.e. CID (CID was defined as a decrease of 100 mL or more from baseline in trough FEV1, an increase of 4 points or more from baseline in SGRQ total score, a TDI focal score of –1 point or less, or a treatment emergent moderate or severe COPD exacerbation occurring up to week 24), all over 24 weeks (Europe and Canada),

Treatment-emergent adverse events (TEAEs)

Results

A total of 3047 patients were screened; out of which 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319).
BGF MDI group demonstrated a significant improvement in the FEV₁ AUC_0-4 versus BFF MDI group (least squares mean difference 104 mL; p<0·0001) and BUD/FORM DPI (91 mL; p<0·0001) over 24 weeks.
At week 24, patients in the BGF MDI group had a significantly improved FEV₁ AUC_0-4 compared with patients receiving BFF MDI (116 mL; p<0·0001)
BGF MDI also significantly improved pre-dose trough FEV₁ versus GFF MDI (22 mL; p=0·0139) and BFF MDI (74 mL; p<0·0001), over 24 weeks.
BGF MDI showed an improvement in the change from baseline in morning pre-dose trough FEV₁ at week 24 versus GFF MDI (13 mL; p=0·2375)

The rate of moderate or severe exacerbations was significantly lower with BGF MDI versus GFF MDI (Table 1)
For time to first moderate or severe exacerbation of COPD, the risk with BGF MDI was nominally significantly lower versus GFF MDI (hazard ratio [HR] 0.593; p<0.0001) and numerically lower versus BFF MDI (HR 0.747; p=0.0635)
BGF MDI significantly improved TDI focal score versus BUD/FORM DPI and provided nominally significant
improvements in change from baseline in RS-Total score over 24 weeks versus GFF MDI (Table 1)
BGF MDI also nominally significant improved SGRQ total score over 24 weeks versus GFF MDI (Table 1)
Time to CID was nominally significantly reduced by BGF MDI versus BFF MDI and BUD/FORM DPI (Table 1)

Table 1: Clinical endpoints with BGF MDI vs dual therapies

	BGF MDI	GFF MDI	BFF MDI	BUD/FORM DPI
Model-estimated rate of moderate or severe COPD exacerbations
Rate, per year	0.46	0.95	0.56	0.55
Rate ratio (95% CI);		0.48 (0.37 to 0.64)	0.82 (0.58 to 1.17)	0.83 (0.59 to 1.18)
p value*		p<0.0001	p=0.2792	p=0.3120
TDI focal score
LSM	1.25	1.07	1.01	0.78
LSM (95% CI)		0.18 (–0.07 to 0.43)	0.24 (–0.07 to 0.54)	0.46 (0.16 to 0.77)
p value*		p=0.1621	p=0.1283	p=0.0031
Change from baseline in RS-Total score
LSM	-1.1	-0.7	-1.0	-1.0
LSM (95% CI)		–0.38 (–0.74 to –0.01)	–0.16 (–0.61 to 0.28)	–0.16 (–0.60 to 0.29)
p value*		p=0.0430†	p=0.4790	p=0.4923
Change from baseline in SGRQ total score
LSM	-7.5	-6.3	-7.1	=6.3
LSM (95% CI)		–1.22 (–2.30 to –0.15)	–0.45 (–1.78 to 0.87)	–1.26 (–2.58 to 0.06)
p value*		p=0.0259†	p=0.5036	p=0.0617
Time to CID
Patients with CID, (%)	64.3	66.1	68.8	70.8
HR (95% CI)		0.88	0.83	0.81
p value*		p=0.0593	p=0,0276†	p=0.0119†

LSM=least squares mean. *Treatment difference for BGF MDI versus comparators. †Nominally significant

The most common treatment-emergent adverse events (TEAEs) were nasopharyngitis and upper respiratory tract infection.
Incidence of pneumonia was low and similar across groups

Conclusions

BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.

Lancet Respir Med. 2018 Oct;6(10):747-758. Doi: 10.1016/S2213-2600(18)30327-8.