Mometasone/Indacaterol/Glycopyrronium (MF/IND/GLY) and MF/IND at Different MF Strengths versus Fluticasone Propionate/Salmeterol Xinafoate (FLU/SAL) and FLU/SAL+ Tiotropium in Patients with Asthma

Figures & data

Table 1 An Overview of Included Studies (PALLADIUM, IRIDIUM, and ARGON)

(A) Study Design and Patient Inclusion Criteria
PALLADIUM^Citation23		IRIDIUM^Citation17			ARGON^Citation21
52-week, multicentre, randomised, double-blind, triple-dummy, parallel-group study		52-week, multicentre, randomised, double-blind, double-dummy, parallel-group, controlled study			24-week, multicentre, randomised, partially blinded, open-label, active-controlled parallel-group, study
Aged ≥12 to ≤75 years		Aged ≥18 to ≤75 years			Aged ≥18 years
Prior medium- or high-dose ICS or low-dose ICS/LABA for ≥3 months and at stable doses for ≥1 month		Prior medium- or high-dose ICS/LABA for ≥3 months and at a stable dose for ≥1 month			Prior medium or high-dose ICS/LABA for ≥3 months and at a stable dose for ≥1 month
Exacerbation history not required		≥1 severe asthma exacerbation in last 12 months			≥1 severe asthma exacerbation in last 12 months
ACQ-7 score: ≥1.5		ACQ-7 score: ≥1.5			ACQ-7 score: ≥1.5
Pre-bronchodilator FEV1% predicted: ≥50% and <85%		Pre-bronchodilator FEV1% predicted: <80%			Pre-bronchodilator FEV1% predicted: <85%
FEV1, reversibility*: Increase in FEV1 of ≥12% and 200 mL		FEV1, reversibility*: Increase in FEV1 of ≥12% and 200 mL			FEV1, reversibility*: Increase in FEV1 of ≥12% and 200 mL
(B) Treatment Arms
	Pooled Analysis of PALLADIUM and IRIDIUM^Citation27(N = 3154)		IRIDIUM^Citation17(N = 1857)^†	ARGON^Citation21(N = 1426)		Total (N = 6437)
Medium-dose MF/IND	1044		–	–		1044
High-dose MF/IND	1054		–	–		1054
Medium-dose MF/IND/GLY	–		620	474		1094
High-dose MF/IND/GLY	–		619	476		1095
High-dose FLU/SAL	1056		618	–		1674
High-dose FLU/SAL + TIO	–		–	476		476

Notes: *After administration of 400 µg salbutamol/360 µg albuterol (or equivalent dose). ^†Patients in the MF/IND arm from the PALLADIUM and IRIDIUM studies are included in the pooled analysis of PALLADIUM and IRIDIUM who had received the same dose of high-dose MF/IND, medium-dose MF/IND, and high-dose FLU/SAL in similar proportion. Medium-dose MF/IND/GLY, MF/IND/GLY 80/150/50 µg o.d.; High-dose MF/IND/GLY, MF/IND/GLY 160/150/50 µg o.d.; Medium-dose MF/IND, MF/IND 160/150 µg o.d.; High-dose MF/IND, MF/IND 320/150 µg o.d.; High-dose FLU/SAL, FLU/SAL 500/50 µg b.i.d; TIO, 5 μg.

Abbreviations: ACQ, Asthma Control Questionnaire; FEV₁, forced expiratory volume in 1 second; MF/IND/GLY, mometasone furoate/indacaterol acetate/glycopyrronium bromide; MF/IND, mometasone furoate/ indacaterol acetate; ICS/LABA, inhaled corticosteroid/long-acting β₂-agonist; o.d., once-daily; FLU/SAL, fluticasone propionate/salmeterol xinafoate; TIO, tiotropium.

Table 2 Baseline Demographics and Clinical Characteristics in the Randomised Set

	PALLADIUM^Citation23 (N = 2216)	IRIDIUM^Citation17 (N = 3092)	ARGON^Citation21 (N = 1426)
Age, years	47.9 ± 14.78	52.2 ± 12.70	52.5 ± 13.33
Female, n (%)	1293 (58)	1918 (62)	902 (63.3)
Never-smoker, n (%)	1812 (82)	2480 (80)	1086 (76.2)
Duration of asthma, years	14.6 ± 12.75	18.1 ± 15.29	20.7 ± 15.33
Baseline ACQ-7 score	2.3 ± 0.48	2.5 ± 0.57	2.6 ± 0.54
Number of asthma exacerbations in the 12 months prior to screening, n (%)
0	1539 (69)	2 (<1)	0
1	534 (24.1)*	2483 (80.0)	1137 (79.7)
2	–	484 (16)	221 (15.5)
3	–	79 (3)	52 (3.6)
≥4	–	44 (1)	16 (1.1)
Prior asthma treatment; n (%)
Low-dose ICS	16 (1)	–	–
Medium-dose ICS	442 (20)	–	–
High-dose ICS	154 (7)	–	–
Low-dose ICS/LABA	1524 (69)	13 (<1)^†	–
Medium-dose ICS/LABA	65 (3)^‡	1928 (62)	700 (49.1)
High-dose ICS/LABA	–	1143 (37)	713 (50.0)
Missing	15 (1%)	8 (<1)	8 (0.6)
Pre-bronchodilator FEV1, % predicted	67.3 ± 8.64	54.8 ± 13.65	62.9 ± 13.89
FEV1 reversibility, % increase	22.8 ± 13.09	27.7 ± 20.15	28.1 ± 17.39

Notes: *>1, 143 (7%), ^†Low-dose ICS/LABA or no dose of ICS/LABA, ^‡Medium- or high-dose ICS/LABA. Data are presented as mean ± SD unless otherwise specified.

Abbreviations: ACQ-7, Asthma Control Questionnaire; FEV₁, forced expiratory volume in 1 second; ICS/LABA, inhaled corticosteroid/long-acting β₂-agonist; N, number of patients.

Table 3 Improvement in Trough FEV₁ with Medium- and High-Dose MF/IND and MF/IND/GLY versus High-Dose FLU/SAL, and Medium- and High-Dose MF/IND/GLY versus High-Dose FLU/SAL + TIO

Treatments	Δ, mL (95% CI); p-value
	Week 26/24*	Week 52
MF/IND versus FLU/SAL
Medium-dose MF/IND versus High-dose FLU/SAL	28 (2 to 55); 0.034	19 (−7 to 45); 0.154
High-dose MF/IND versus High-dose FLU/SAL	43 (17 to 69); 0.001	51 (25 to 77); <0.001
MF/IND/GLY versus FLU/SAL
Medium-dose MF/IND/GLY versus High-dose FLU/SAL	99 (64 to 133); <0.001	87 (52 to 122); 0.001
High-dose MF/IND/GLY versus High-dose FLU/SAL	119 (85 to 154); <0.001	145 (111 to 180); <0.001
MF/IND/GLY versus FLU/SAL+ TIO*
Medium-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	9 (−41 to 60); 0.713	-
High-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	96 (46 to 146); <0.001	-

Notes: All comparisons presented are not adjusted for multiplicity, and therefore, p-values are nominal. *MF/IND/GLY versus FLU/SAL + TIO comparison was evaluated at Week 24. Medium-dose MF/IND/GLY, MF/IND/GLY 80/150/50 µg o.d.; high-dose MF/IND/GLY, MF/IND/GLY 160/150/50 µg o.d.; medium-dose MF/IND, MF/IND 160/150 µg o.d.; high-dose MF/IND, MF/IND 320/150 µg o.d.; high-dose FLU/SAL, FLU/SAL 500/50 µg b.i.d.; TIO, 5 µg o.d.

Abbreviations: Δ, LS mean treatment difference; b.i.d., twice-daily; FEV₁, forced expiratory volume in 1 second; LS, least square; MF/IND, mometasone furoate/indacaterol acetate; MF/IND/GLY, mometasone furoate/indacaterol acetate/glycopyrronium bromide; o.d., once-daily; FLU/SAL, fluticasone propionate/salmeterol xinafoate; TIO, tiotropium.

Table 4 Improvement in Peak Expiratory Flow (PEF) with High-Dose MF/IND and Medium- and High-Dose MF/IND/GLY versus High-Dose FLU/SAL Over 52 Weeks and Medium- and High-Dose MF/IND/GLY versus FLU/SAL + TIO Over 24 Weeks

Treatment	Morning PEF	Evening PEF
	Δ, L/min (95% CI); p-value
MF/IND versus FLU/SAL
High-dose MF/IND versus High-dose FLU/SAL	14.5 (9.7 to 19.3); <0.001	11 (6.2 to 15.7); <0.001
MF/IND/GLY versus FLU/SAL
Medium-dose MF/IND/GLY versus High-dose FLU/SAL	28.5 (23.2 to 33.8); <0.001	25.8 (20.5 to 31.0); <0.001
High-dose MF/IND/GLY versus High-dose FLU/SAL	34.8 (29.5 to 40.1); <0.001	29.5 (24.2 to 34.7); <0.001
MF/IND/GLY versus FLU/SAL+ TIO*
Medium-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	5.9 (0.3 to 11.6); 0.038	2.7 (−2.8 to 8.2); 0.335
High-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	11.8 (6.1 to 17.4); <0.001	9.8 (4.3 to 15.3); <0.001

Notes: All comparisons presented are not adjusted for multiplicity, and therefore, p-values are nominal. *Data analysed over 17 to 24 weeks. Medium-dose MF/IND/GLY, MF/IND/GLY 80/150/50 µg o.d.; High-dose MF/IND/GLY, MF/IND/GLY 160/150/50 µg o.d.; High-dose MF/IND, MF/IND 320/150 µg o.d.; High-dose FLU/SAL, FLU/SAL 500/50 µg b.i.d.; TIO, TIO 5 µg o.d.

Abbreviations: Δ, LS mean treatment difference; b.i.d., twice-daily; MF/IND, mometasone furoate/indacaterol acetate; MF/IND/GLY, mometasone furoate/indacaterol acetate/glycopyrronium bromide; LS, least square; PEF, peak expiratory flow, TIO, tiotropium; o.d., once-daily; FLU/SAL, fluticasone propionate/salmeterol xinafoate.

Table 5 Improvement in ACQ-7 Scores and Proportion of Patients Achieving MCID Improvement in ACQ-7 Scores (ACQ Responders) with MF/IND and Medium- and High-Dose MF/IND/GLY versus High-Dose FLU/SAL and Medium- and High-Dose MF/IND/GLY versus High-Dose FLU/SAL + TIO at Different Time Points

Treatment	Week 26/24*	Week 52
ACQ-7 Score	Δ (95% CI); p-value
MF/IND versus FLU/SAL
Medium-dose MF/IND versus High-dose FLU/SAL	−0.043 (−0.105 to 0.018); 0.169	−0.015 (−0.077 to 0.048); 0.646
High-dose MF/IND versus High-dose FLU/SAL	−0.091 (−0.153 to −0.030); 0.004	−0.041 (−0.104 to 0.021); 0.197
MF/IND/GLY versus FLU/SAL
Medium-dose MF/IND/GLY versus High-dose FLU/SAL	–0.084 (–0.164 to –0.005); 0.038	0.008 (−0.073 to 0.090); 0.845
High-dose MF/IND/GLY versus High-dose FLU/SAL	–0.086 (–0.165 to –0·006); 0.034	−0.121 (−0.202 to −0.040); 0.003
MF/IND/GLY versus FLU/SAL+ TIO*
Medium-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	−0.032 (−0.125 to 0.060); 0.245	-
High-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	−0.124 (−0.216 to −0.032); 0.004	-
ACQ-7 responder (≥0.5-point reduction from baseline)	Odds ratio (95% CI); p-value
MF/IND versus FLU/SAL
Medium-dose MF/IND versus High-dose FLU/SAL	1.05 (0.86 to 1.28); 0.648	1.07 (0.86 to 1.32); 0.564
High-dose MF/IND versus High-dose FLU/SAL	1.20 (0.98 to 1.47); 0.083	1.17 (0.94 to 1.45); 0.154
MF/IND/GLY versus FLU/SAL
Medium-dose MF/IND/GLY versus High-dose FLU/SAL	1.20 (0.92 to 1.57); 0.17	0.99 (0.75 to 1.29); 0.922
High-dose MF/IND/GLY versus High-dose FLU/SAL	1.21 (0.93 to 1.57); 0.15	1.41 (1.06 to 1.86); 0.017
MF/IND/GLY versus FLU/SAL+ TIO*
Medium-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	1.23 (0.94 to 1.61); 0.061	-
High-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	1.11 (0.85 to 1.46); 0.227	-

Notes: *Data analysed at Week 24. All comparisons presented are not adjusted for multiplicity, and therefore, p-values are nominal. Medium-dose MF/IND/GLY, MF/IND/GLY 80/150/50 µg o.d.; high-dose MF/IND/GLY, MF/IND/GLY 160/150/50 µg o.d.; medium-dose MF/IND, MF/IND 160/150 µg o.d.; high-dose MF/IND, MF/IND 320/150 µg o.d.; high-dose FLU/SAL, FLU/SAL 500/50 µg b.i.d.; TIO, TIO 5 µg o.d.

Abbreviations: Δ, LS mean treatment difference; ACQ, Asthma Control Questionnaire; b.i.d., twice-daily; LS, least square; MF/IND, mometasone furoate/indacaterol acetate; MF/IND/GLY, mometasone furoate/indacaterol acetate/glycopyrronium bromide; TIO, tiotropium; o.d., once-daily; FLU/SAL, fluticasone propionate/salmeterol xinafoate.

Table 6 Reduction in Annualised Rate of Moderate or Severe, Severe, and All (Mild. Moderate, Severe) Exacerbations with Medium- and High-Dose of MF/IND and MF/IND/GLY versus High-Dose FLU/SAL and with MF/IND/GLY versus High-Dose FLU/SAL + TIO

Treatment	Moderate or Severe Exacerbations	Severe Exacerbations	All (mild. Moderate, severe) exacerbations
	Rate Ratio (95% CI); p-value
MF/IND versus FLU/SAL
Medium-dose MF/IND versus High-dose FLU/SAL	0.94 (0.79 to 1.12); 0.479	0.91 (0.75 to 1.11); 0.359	0.84 (0.72 to 0.98); 0.024
High-dose MF/IND versus High-dose FLU/SAL	0.78 (0.66 to 0.93); 0.006	0.74 (0.61 to 0.91); 0.004	0.81 (0.70 to 0.94); 0.006
MF/IND/GLY versus FLU/SAL
Medium-dose MF/IND/GLY versus High-dose FLU/SAL	0.81 (0.66 to 0.99); 0.041	0.84 (0.67 to 1.05); 0.117	0.70 (0.58 to 0.84); <0.001
High-dose MF/IND/GLY versus High-dose FLU/SAL	0.64 (0.52 to 0.78); <0.001	0.58 (0.45 to 0.73); <0.001	0.60 (0.50 to 0.72); <0.001
MF/IND/GLY versus FLU/SAL+ TIO*
Medium-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	1.04 (0.77 to 1.39); 0.798	1.22 (0.85 to 1.75); 0.282	1.01 (0.79 to 1.31); 0.915
High-dose MF/IND/GLY versus High-dose FLU/SAL + TIO	0.88 (0.65 to 1.19); 0.414	1.14 (0.79 to 1.64); 0.494	0.81 (0.62 to 1.06); 0.123

Notes: Data are presented as annualised rate (95% CI); error bars represent CI values. All comparisons presented are not adjusted for multiplicity, and therefore, p-values are nominal. *Comparisons were analysed over 24 weeks. Medium-dose MF/IND/GLY, MF/IND/GLY 80/150/50 µg o.d.; high-dose MF/IND/GLY, MF/IND/GLY 160/150/50 µg o.d.; medium-dose MF/IND, MF/IND 160/150 µg o.d.; High-dose MF/IND, MF/IND 320/150 µg o.d.; high-dose FLU/SAL, FLU/SAL 500/50 µg b.i.d.; TIO, 5 µg o.d.

Abbreviations: b.i.d., twice-daily; MF/IND, indacaterol acetate/mometasone furoate; MF/IND/GLY, mometasone furoate/indacaterol acetate/glycopyrronium bromide; TIO, tiotropium; o.d., once-daily; FLU/SAL, fluticasone propionate/salmeterol xinafoate.

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