Imidafenacin, An Orally Active Muscarinic Receptor Antagonist, Improves Pulmonary Function In Patients With Chronic Obstructive Pulmonary Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 3×3 Crossover Phase II Trial

Figures & data

Figure 1 Study design. After screening visit (S), eligible patients were randomized (R) to three 1-day treatment periods. The treatments comprised a single oral dose of imidafenacin 0.1 mg, imidafenacin 0.2 mg, or placebo.

Table 1 Baseline Characteristics Of Patients

Characteristics (RDN)	n=27
Male, n (%)	27 (100.0)
Age, years	69.9 ± 5.9
Duration of COPD, months	30.3 ± 28.3
Use of regular respiratory medicines at screening visit, n (%)
Any	26 (96.3)
Long-acting muscarinic antagonists	21 (77.8)
Long-acting b2 agonists	15 (55.6)
Inhaled corticosteroids	10 (37.0)
Slow release theophylline	4 (14.8)
Mucolytic agents	3 (11.1)
Smoking index, pack-years	61.0 ± 31.8
Pulmonary function tests
%FEV1 predicted, %	53.4 ± 12.0
Stage III (30% ≤ %FEV1 predicted < 50%)	11 (40.7)
Stage II (50% ≤ %FEV1 predicted < 80%)	16 (59.3)
Ratio of FEV1/FVC, %	46.8 ± 10.3

Notes: The analyses were used data of all randomized patients set. All data were expressed as mean ± SD and number (%) of patients. Data of pulmonary function tests were obtained 30 mins after inhaled short-acting β₂-agonists.

Abbreviations: FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; RND, all randomized patients; SD, standard deviation.

Figure 2 Analyses for the enrolled subjects.

Table 2 Changes In FEV₁ After Oral Imidafenacin When Compared With Placebo

Treatments	Mean (SEM)	Point Estimation [95% CI]	p Value
(A) Maximum Changes in FEV1 (L) From Baseline during 24 hrs After Administration
Placebo	0.09 (0.01)	–	–
Imidafenacin 0.1 mg	0.15 (0.02)	0.06 [0.01, 0.11]	0.0286*
Imidafenacin 0.2 mg	0.17 (0.02)	0.09 [0.03, 0.14]	0.0017*
(B) AUC of FEV1 (L·H) From Baseline During 24 hrs After Administration
Placebo	31.76 (1.83)	–	–
Imidafenacin 0.1 mg	32.56 (1.80)	0.91 [−0.09, 1.91]	0.0729
Imidafenacin 0.2 mg	33.48 (1.80)	1.25 [0.23, 2.26]	0.0175*

Notes: Number of subjects were 24 as per protocol set. Point estimation [95% CI] of maximum changes in FEV₁ and AUC_24h of FEV₁ with imidafenacin 0.1 and 0.2 mg were compared to that with placebo by ANCOVA tests, which included this endpoint as the response variable, each baseline value at each test period as covariates, test drug effects, group effects, and period effects as factors, and subjects as random effects. *P <0.05 versus placebo.

Abbreviations: ANCOVA, analysis of covariance; AUC, area under the curve; CI, confidence interval; FEV₁, forced expiratory volume in 1 s; SEM, standard error of mean.

Figure 3 Temporal changes in FEV₁ (L). The monitoring period was 24 hrs beginning at the time of oral administration of imidafenacin (analysis set: PPS). All data were represented as means ± SEM. *P<0.05 versus placebo at each time period.

Abbreviations: BL, baseline; FEV₁, forced expiratory volume in 1 s; PPS, per protocol set; SEM, standard error of mean.

Figure 4 Pharmacokinetic data of plasma concentrations of imidafenacin. Sample sizes as full analysis set of imidafenacin 0.1 mg and 0.2 mg were 26 and 27, respectively. Data were plotted as circles. Standard deviations were expressed as bars.

Figure 5 Relationship between plasma imidafenacin concentration and change in FEV₁. Plasma imidafenacin level was positively correlated with change in FEV₁ during the 24-hrs period immediately after imidafenacin administration. Data represent mean values for all patients at each time point.

Abbreviation: FEV₁, forced expiratory volume in 1 s.

Table 3 Summary of Adverse Events

Treatments	Placebo	Imidafenacin 0.1 mg	Imidafenacin 0.2 mg
n, SAF	27	26	27
Total occurrence, n (%)	0 (0)	2 (7.7)	3 (11.1)
Dry mouth	0 (0)	0 (0)	1 (3.7)
Thirst	0 (0)	1 (3.8)	0 (0)
Muscle stiffness	0 (0)	0 (0)	1 (3.7)
ECG T-wave inversion	0 (0)	1 (3.8)	0 (0)
Insomnia	0 (0)	0 (0)	1 (3.7)
Skin exfoliation	0 (0)	0 (0)	1 (3.7)

Abbreviations: ECG, electrocardiogram; SAF, safety analysis set.