Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD

Figures & data

Figure 1 Patient disposition.

Note: All patients who discontinued treatment early due to protocol criteria had a moderate or severe COPD exacerbation (n=18), an acute exacerbation of chronic bronchitis (n=1), or they did not meet baseline FEV₁ stability criteria (n=5).
Abbreviations: BD, budesonide; BFF, budesonide/formoterol fumarate; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; MDI, metered dose inhaler.

Table 1 Baseline demographics and clinical characteristics (safety/ITT population)

Parameter	BFF MDI 320/9.6 µg, n=155	BFF MDI 160/9.6 µg, n=106	BFF MDI 80/9.6 µg, n=103	BD MDI 320 µg, n=108	FF MDI 9.6 µg, n=157	All patients, N=180
Mean age, years (SD)	61.7 (8.5)	61.8 (8.0)	61.7 (8.7)	62.3 (8.2)	62.4 (8.6)	62.2 (8.4)
Mean BMI, kg/m^2 (SD)	28.4 (6.5)	27.4 (5.7)	28.5 (6.4)	28.4 (6.4)	28.3 (6.2)	28.3 (6.4)
Gender, % male	45.2	49.1	44.7	45.4	46.5	46.7
Race, %
Caucasian	89.0	90.6	88.3	90.7	88.5	90.0
Black or African-American	11.0	9.4	11.7	9.3	11.5	10.0
Smoking status, % current	63.9	66.0	60.2	63.0	62.4	61.1
Mean smoking history, pack-years (SD)	49.5 (23.0)	50.5 (23.6)	48.6 (22.4)	51.3 (23.1)	50.7 (23.1)	50.8 (23.2)
COPD severity,a % severeb	40.6	47.2	38.8	39.8	42.0	42.8
Mean duration of COPD, years (SD)	8.1 (5.3)	8.3 (4.9)	7.5 (5.4)	8.2 (5.3)	8.2 (5.2)	8.2 (5.2)
Prior medication use,c n (%)
LAMA	14 (9.0)	10 (9.4)	10 (9.7)	7 (6.5)	16 (10.2)	18 (10.0)
ICS	10 (6.5)	7 (6.6)	7 (6.8)	7 (6.5)	11 (7.0)	11 (6.1)
LAMA/LABA FDC	1 (0.6)	1 (0.9)	1 (1.0)	0	1 (0.6)	1 (0.6)
ICS+LABAd	27 (17.4)	17 (16.0)	19 (18.4)	22 (20.4)	26 (16.6)	33 (18.3)
ICS+LAMAe	2 (1.3)	2 (1.9)	1 (1.0)	1 (0.9)	2 (1.3)	2 (1.1)
ICS+LAMA+LABAe	16 (10.3)	11 (10.4)	11 (10.7)	10 (9.3)	18 (11.5)	22 (12.2)
Exacerbation history,f n (%) [number of events]
Moderateg	16 (10.3) [24]	12 (11.3) [13]	9 (8.7) [15]	12 (11.1) [19]	15 (9.6) [21]	18 (10.0) [26]
Severeh	2 (1.3) [5]	1 (0.9) [1]	2 (1.9) [5]	1 (0.9) [4]	2 (1.3) [5]	2 (1.1) [5]
Mean SAC BDI scorei (SD)	7.0 (2.1)	6.9 (2.1)	7.2 (2.2)	6.9 (2.0)	7.0 (2.2)	7.0 (2.0)
Mean baseline daily puffs of albuterolj (SD)	2.7 (3.3)	3.1 (3.7)	2.5 (2.7)	2.9 (3.5)	2.7 (3.2)	2.8 (3.3)
Mean screening FEV1, % predicted (SD)
Pre-bronchodilator	46.4 (12.6)	45.0 (12.7)	47.5 (12.4)	46.4 (12.5)	46.3 (12.4)	46.2 (12.3)
Post-bronchodilator	53.1 (12.6)	51.5 (12.3)	53.6 (12.6)	53.4 (12.8)	52.9 (12.5)	52.7 (12.3)
Mean screening FEV1, L (SD)
Pre-bronchodilator	1.318 (0.456)	1.312 (0.497)	1.350 (0.424)	1.306 (0.430)	1.305 (0.440)	1.318 (0.456)
Post-bronchodilator	1.512 (0.490)	1.502 (0.523)	1.528 (0.458)	1.506 (0.467)	1.496 (0.474)	1.506 (0.488)
Mean reversibility,k % (SD)	16.3 (13.1)	16.6 (13.9)	14.1 (11.2)	16.8 (13.4)	16.1 (13.4)	15.8 (13.0)

Notes:

a Severity of COPD was based on the non-missing post-bronchodilator assessment at screening.

b 30%≤FEV₁<50% predicted (GOLD 3).¹

c During the 2-week period prior to Visit 1. If a patient was on an FDC therapy and monotherapy component of the combination during the period of interest, the patient was categorized as being on the combination. Only data for long-acting therapies are shown.

d Delivered as an FDC or via separate inhalers.

e Delivered via separate inhalers.

f Within the past 12 months of the screening visit.

g Treated with systemic (oral or intravenous) corticosteroids and/or antibiotics.

h Resulted in hospital admission or emergency room treatment.

i ITT population: n=152, n=100, n=99, n=103, n=148, n=171.

j Obtained using the non-missing values from the last 7 days prior to randomization.

k Defined as ([the change from pre-bronchodilator to post-bronchodilator FEV₁]/pre-bronchodilator FEV₁)×100.

Abbreviations: BD, budesonide; BDI, Baseline Dyspnea Index; BFF, budesonide/formoterol fumarate; BMI, body mass index; FDC, fixed-dose combination; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; ITT, intent-to-treat; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; MDI, metered dose inhaler; SAC, self-administered computerized.

Figure 2 FEV₁ AUC_0–12 on Day 29 (mITT population).

Notes: ^‡p<0.0001 versus BD MDI; p=0.0013 versus FF MDI; ^§p<0.0001 versus BD MDI; p=0.2827 versus FF MDI; ^¶p<0.0001 versus BD MDI; p=0.1436 versus FF MDI. Error bars represent 95% CI.
Abbreviations: AUC_0–12, area under the curve from 0 to 12 hours; BD, budesonide; BFF, budesonide/formoterol fumarate; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat.

Table 2 Summary of secondary efficacy endpoints (mITT population)

Parameter	LSM	LSM differences between treatments
		BD MDI 320 µg	FF MDI 9.6 µg
Change from baseline in morning pre-dose trough FEV1 over 28 days, mL
BFF MDI 320/9.6 μg, n=151		n=102	n=147
LSM (95% CI)	138 (111, 165)	115‡ (81, 150)	55*** (24, 86)
BFF MDI 160/9.6 μg, n=100
LSM (95% CI)	121 (89, 153)	99‡ (60, 137)	38* (3, 73)
BFF MDI 80/9.6 μg, n=97
LSM (95% CI)	110 (78, 142)	88‡ (49, 127)	27 (−8, 63)
FVC AUC0–12 on Day 29, mL
BFF MDI 320/9.6 μg, n=148		n=99	n=142
LSM (95% CI)	305 (244, 365)	303‡ (229, 376)	52 (−13, 117)
BFF MDI 160/9.6 μg, n=98
LSM (95% CI)	245 (176, 315)	244‡ (161, 327)	−7 (−82, 68)
BFF MDI 80/9.6 μg, n=96
LSM (95% CI)	267 (196, 337)	265‡ (182, 348)	14 (−60, 89)
SAC TDI focal score on Day 29
BFF MDI 320/9.6 μg, n=149		n=100	n=142
LSM (95% CI)	0.598 (0.298, 0.899)	0.707** (0.285, 1.130)	0.339 (−0.039, 0.717)
BFF MDI 160/9.6 μg, n=97
LSM (95% CI)	0.882 (0.518, 1.246)	0.992‡ (0.516, 1.467)	0.623** (0.190, 1.056)
BFF MDI 80/9.6 μg, n=96
LSM (95% CI)	0.459 (0.093, 0.825)	0.568* (0.091, 1.045)	0.200 (−0.233, 0.632)
Change from baseline in mean daily number of puffs of rescue medication over the last week of treatment
BFF MDI 320/9.6 μg, n=152		n=104	n=149
LSM (95% CI)	0.05 (–0.34, 0.43)	−0.92‡ (−1.29, −0.54)	−0.40* (−0.73, −0.07)
BFF MDI 160/9.6 μg, n=101
LSM (95% CI)	0.16 (−0.27, 0.58)	−0.81*** (−1.23, −0.39)	−0.29 (−0.67, 0.09)
BFF MDI 80/9.6 μg, n=98
LSM (95% CI)	0.24 (−0.19, 0.67)	−0.73*** (−1.15, −0.30)	−0.21 (−0.59, 0.17)

Notes:

* p<0.05,

** p<0.01,

*** p<0.001,

‡ p<0.0001.

Abbreviations: AUC_0–12, area under the curve from 0 to 12 hours; BD, budesonide; BFF, budesonide/formoterol fumarate; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; FVC, forced vital capacity; LSM, least squares mean; MDI, metered dose inhaler; mITT, modified intent-to-treat; SAC, self-administered computerized; TDI, Transition Dyspnea Index.

Figure 3 Peak change from baseline in FEV₁ over 28 days (mITT population).

Notes: Error bars represent standard error. The LSM treatment difference between all doses of BFF MDI and BD MDI 320 μg was significant (p<0.0001) for all time points and over 28 days. The LSM treatment difference between BFF MDI and FF MDI 9.6 μg was significant (p<0.05) for BFF MDI 320/9.6 μg and BFF MDI 160/9.6 μg on Day 15 and over 28 days, and for BFF MDI 320/9.6 μg on Day 29.
Abbreviations: BD, budesonide; BFF, budesonide/formoterol fumarate; FEV₁, forced expiratory volume in 1 second; FF, formoterol fumarate; LSM, least squares mean; mITT, modified intent-to-treat; MDI, metered dose inhaler.

Table 3 Summary of TEAEs overall and by treatment group (safety population)a

Parameter, n (%)	BFF MDI 320/9.6 µg, n=155	BFF MDI 160/9.6 µg, n=106	BFF MDI 80/9.6 µg, n=103	BD MDI 320 µg, n=108	FF MDI 9.6 µg, n=157	All patients, N=180
Patients with at least one TEAE	36 (23.2)	20 (18.9)	22 (21.4)	28 (25.9)	31 (19.7)	96 (53.3)
Patients with TEAEs relatedb to study treatment	5 (3.2)	3 (2.8)	4 (3.9)	6 (5.6)	3 (1.9)	19 (10.6)
Patients with serious TEAEs	2 (1.3)	0	3 (2.9)	3 (2.8)	1 (0.6)	9 (5.0)
Patients with serious TEAEs relatedb to study treatment	0	0	2 (1.9)	0	0	2 (1.1)
Patients with TEAEs that led to early discontinuation	1 (0.6)	0	3 (2.9)	2 (1.9)	0	6 (3.3)
TEAEs (preferred term) reported in ≥2% patients in any treatment group
Nasopharyngitis	5 (3.2)	1 (0.9)	2 (1.9)	2 (1.9)	5 (3.2)	13 (7.2)
Hypertension	2 (1.3)	1 (0.9)	1 (1.0)	3 (2.8)	2 (1.3)	9 (5.0)
Cough	1 (0.6)	0	1 (1.0)	3 (2.8)	1 (0.6)	6 (3.3)
Upper respiratory tract infection	4 (2.6)	0	1 (1.0)	0	0	5 (2.8)

Notes:

a These data do not include TEAEs with onset during the washout periods.

b Judged by the investigator to be possibly, probably, or definitely related.

Abbreviations: BD, budesonide; BFF, budesonide/formoterol fumarate; FF, formoterol fumarate; MDI, metered dose inhaler; TEAE, treatment-emergent adverse event.

Figure 4 Relative bioavailability of budesonide and formoterol on Day 29 (PK population).

Notes: Vertical bars are 90% CI of the ratio (combination/monocomponent) of geometric LSM. Dashed lines represent the predefined bounds of 80%–125% for the point estimate for the ratio, and 75% and 133% for the 90% CIs.
Abbreviations: AUC_0–12, area under the curve from 0 to 12 hours; BD, budesonide; BFF, budesonide/formoterol fumarate; C_max, maximum observed plasma concentration; FF, formoterol fumarate; LSM, least squares mean; MDI, metered dose inhaler; PK, pharmacokinetic.

Global Initiative for Chronic Obstructive Lung Disease [homepage on the Internet]Global Strategy for the Diagnosis, Management and Prevention of COPD [updated 2018] Available from: http://www.goldcopd.orgAccessed November 15, 2017

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