Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA

Figures & data

Figure 1 Hypothesis for the mode of action of roflumilast.

Abbreviations: FEV₁, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist.

Table 1 Patient characteristics and demographics after randomization

	Roflumilast			Placebo
	Total	Responders	Nonresponders
Length (cm)	166.2±6.44	166.75±7.77	165.90±5.90	170.06±10.56
Pack-years smoking (years)	53.13±35.57	73.94±46.99	42.03±22.48	54.83±30.24
Age (years)	63.61±7.38	62.12±6.94	64.40±7.73	70±6.76
Weight (kg)	84.08±28.58	87.90±35.45	82.04±25.35	92.81±26.18
FVC (%pred)	79.76±21.08	82.24±23.62	78.44±20.35	79.97±13.43
FEV1 (%pred)	41.3±12.17	46.91±11.04	38.31±12.01	47.28±11.19
FEV1/FVC (%)	42.5±12.62	47.64±12.33	39.77±12.29	46.61±10.41
RV (%pred)	171.32±35.31	168.21±24.48	172.97±40.64	146.36±28.26
TLC (%pred)	114.44±21.39	112.26±20.69	115.61±22.39	106.22±11.02
FRC (%pred)	147.22±33.72	144.88±26.69	148.47±37.76	130.94±25.07
Raw (kPas/L)	0.77±0.3	0.71±0.24	0.80±0.33	0.67±0.35
sRaw (kPas)	3.97±1.96	3.43±0.91	4.24±2.30	3±1.26
LCI (units)	8.87±1.33	8.63±1.21	9.02±1.44	9.16±1.94
Nitrogen washout time (min)	5.48±2.51	5.22±2.66	5.64±2.56	3.46±1.16
6MWT (m)	357.53±90.02	393.83±84.48	340.77±90.66	403.88±148.84

Note: Data presented as mean ± standard deviation.

Abbreviations: 6MWT, 6-minute walk test; %pred, percentage of predicted; FEV₁, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; LCI, lung clearance index; Raw, airways resistance; RV, residual volume; sRaw, specific airways resistance; TLC, total lung capacity.

Figure 2 CONSORT diagram of the clinical trial.

Abbreviations: CONSORT, CONsolidated Standards Of Reporting Trials; qd, once daily.

Figure 3 Regional hyperinflation at the FRC level for a COPD patient from the roflumilast trial and a healthy volunteer (both female, both 170 cm in height).

Abbreviations: %p, percentage of predicted; COPD, chronic obstructive pulmonary disease; FRC, functional residual capacity.

Table 2 Aerosol characteristics of LAMA and LABA/ICS used in the FRI deposition calculations

Inhaler	MMAD	GSD	FPF (%)
Spiriva (LAMA)^Citation26	3.9	1.8	23.21
Onbrez (LABA)^Citation26	3.2	2	39.41
Oxis (LABA)^Citation27	2.13	1.72	69.06
Pulmicort (ICS)^Citation28	1.9	2.1	48
Seretide Diskus (ICS/LABA)^Citation29
ICS	3.54	1.49	21.6
LABA	3.57	1.46	23.34
Symbicort (ICS/LABA)^Citation29
ICS	3.30	1.57	38.71
LABA	3.09	1.56	43.73
Inuvair MDI (ICS/LABA)^Citation30
ICS	1.3	1.97	38.07
LABA	1.3	2.00	39.47
Seretide MDI (ICS/LABA)^Citation31
ICS	3.5	1.9	42.06
LABA	3.4	1.9	42.94

Abbreviations: FPF, fine particle fraction; FRI, functional respiratory imaging; GSD, geometric standard deviation; ICS, inhaled corticosteroid; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist; MDI, metered dose inhaler; MMAD, mass mean aerodynamic diameter.

Figure 4 Negative correlation between the lobar blood vessel density and the change in lobar hyperinflation in the roflumilast responder group after 6 months of treatment.

Note: Better-perfused lobes experience larger reduction in hyperinflation.

Abbreviation: %p, percentage of predicted.

Figure 5 No correlation between the lobar blood vessel density and the change in lobar hyperinflation in the placebo group.

Abbreviation: %p, percentage of predicted.

Figure 6 Negative correlation between the change in lobar hyperinflation and the change in lobar ventilation in the Roflumilast responder group after 6 months of treatment.

Note: Lobes that experience a larger reduction in hyperinflation are better ventilated.

Abbreviation: %p, percentage of predicted.

Figure 7 Positive correlation between the change in lobar ventilation and the change in lobar aerosol deposition in the roflumilast responder group after 6 months of treatment.

Note: Lobes that are better ventilated consequently experience more drug deposition.

Figure 8 Positive correlation between the change in lobar aerosol deposition and the change in lobar CT-based bronchodilation (iVaw) in the roflumilast responder group after 6 months of treatment.

Note: Lobes with higher deposition had more bronchodilation.

Abbreviations: CT, computed tomography; iVaw, image-based airway volume.

Figure 9 Positive correlation between the change in CT-based bronchodilation (iVaw) and the observed changes in FEV₁.

Note: More bronchodilation leads to better FEV₁.
Abbreviations: CT, computed tomography; FEV₁, forced expiratory volume in 1 second; iVaw, image-based airway volume; %p, percentage of predicted.

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