Cardiovascular Safety of QVA149, a Combination of Indacaterol and NVA237, in COPD Patients

Figures & data

Table 1.  Patient baseline demographics and characteristics (Safety population)

	QVA149			Indacaterol	Placebo
	600/100 μg	300/100 μg	150/100 μg	300 μg
	N = 49	N = 51	N = 51	N = 51	N = 53
Age, years
mean ± SD	65.7 ± 9.34	63.7 ± 8.94	60.9 ± 8.58	64.5 ± 9.75	64.3 ± 8.95
Male, n (%)	38 (77.6)	41 (80.4)	36 (70.6)	41 (80.4)	39 (73.6)
Race, n (%)
Caucasian	49 (100.0)	50 (98.0)	51 (100.0)	49 (96.1)	53 (100.0)
Duration of COPD, years
mean ± SD	6.1 ± 4.60	7.0 ± 6.42	5.9 ± 3.62	7.5 ± 6.88	7.5 ± 5.45
Smoking history, n (%)
Ex-smoker	31 (63.3)	36 (70.6)	32 (62.7)	37 (72.5)	34 (64.2)
Current smoker	18 (36.7)	15 (29.4)	19 (37.3)	14 (27.5)	19 (35.8)
Previous use of COPD medications, n (%)
long-acting anti- cholinergics (tiotropium)	24 (49.0)	17 (33.3)	20 (39.2)	22 (43.1)	26 (49.1)
long-acting β2-agonists	10 (20.4)	6 (11.8)	8 (15.7)	10 (19.6)	7 (13.2)
Estimated number of pack years, mean ± SD	46.1 ± 26.78	42.2 ± 21.20	39.6 ± 15.60	43.5 ± 23.89	50.2 ± 37.70
FEV1*, L
mean ± SD	1.4±0.41	1.6 ± 0.52	1.5 ± 0.54	1.6 ± 0.46	1.43 ± 0.398
FEV1% predicted
mean ± SD	45.2 ± 12.61	49.1 ± 14.92	48.0 ± 14.06	48.0 ± 12.79	46.7 ± 12.19
FEV1 reversibility,%
mean ± SD	14.9 ± 11.93	15.3 ± 17.24	10.7 ± 14.37	13.6 ± 11.07	15.0 ± 14.56
FEV1/FVC*,%
mean ± SD	49.6 ± 8.96	51.1 ± 11.22	48.5 ± 10.01	51.1 ± 11.72	49.6 ± 9.48

*Measured post-bronchodilator (salbutamol).

Figure 1.  Subject disposition.

Table 2.  Patient cardiovascular baseline characteristics (Safety population)

	QVA149			Indacaterol	Placebo
	600/100 μg	300/100 μg	150/100 μg	300 μg
	N = 49	N = 51	N = 51	N = 51	N = 53
24-h heart rate, bpm
mean ± SD	78.6 ± 10.86	80.6 ± 8.00	82.0 ± 10.72	78.2 ± 10.81	78.8 ± 9.13
Pulse, bpm
mean ± SD	77.4 ± 12.62	76.0 ± 11.29	78.8 ± 11.80	77.1 ± 9.78	78.3 ± 12.39
Systolic blood pressure, mmHg
mean ± SD	136.4 ± 15.68	127.9 ± 15.21	132.3 ± 14.21	130.9 ± 14.59	132.3 ± 16.66
Diastolic blood pressure, mmHg
mean ± SD	79.9 ± 9.48	78.2 ± 7.79	80.8 ± 8.69	78.4 ± 8.98	77.6 ± 8.81
ECG overall interpretation, n(%)
Normal	36 (75.0)	36 (70.6)	41 (80.4)	35 (68.6)	44 (83.0)
Clinically insignificant abnormality	11 (22.9)	15 (29.4)	9 (17.6)	16 (31.4)	9 (17.0)
Clinically significant abnormality	1 (2.1)	0 (0.0)	1 (2.0)	0 (0.0)	0 (0.0)
QTc Fridericia, ms
mean ± SD	406.8 ± 19.53	401.3 ± 20.38	402.6 ± 19.03	404.5 ± 22.40	404.3 ± 18.08

Figure 2.  Change from baseline in 24-hr mean heart rate (bpm) on Day 14. Data are least squares mean and the corresponding 98.3% CIs and 95% CIs versus placebo and indacaterol, respectively; p > 0.05 for all doses.

Table 3.  Overall incidence of notable QTc values, change from baseline and most significant ECG results (Safety population), n (%)

	QVA149			Indacaterol	Placebo
	600/100 μg	300/100 μg	150/100 μg	300 μg
	N = 49	N = 51	N = 51	N = 51	N = 53
Total no. patients QTc determination	49	51	51	51	53
Male	38	41	36	41	39
Female	11	10	15	10	14
QTc (Fridericia's formula) –maximum post-baseline value
QTc >450 ms (male)	6 (15.8)	4 (9.8)	1 (2.8)	2 (4.9)	3 (7.7)
QTc >470 ms (female)	0 (0.0)	0 (0.0)	0 (0.0)	1 (10.0)	0 (0.0)
Total notable	6 (12.2)	4 (7.8)	1 (2.0)	3 (5.9)	3 (5.7)
QTc (Fridericia's formula) –maximum increase from baseline
<30 ms	39 (79.6)	40 (78.4)	42 (84.0)	41 (80.4)	51 (96.2)
30–60 ms	10 (20.4)	11 (21.6)	8 (16.0)	10 (19.6)	1 (1.9)
>60 ms	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.9)
Most significant ECG result –post-baseline
Normal	20 (40.8)	23 (45.1)	30 (58.8)	28 (54.9)	34 (64.2)
Clinically insignificant abnormality	28 (57.1)	28 (54.9)	20 (39.2)	23 (45.1)	19 (35.8)
Clinically significant abnormality	1 (2.0)	0 (0.0)	1 (2.0)	0 (0.0)	0 (0.0)

Percentages were calculated based on the number of patients having the specific assessment at baseline (where needed) and at least one post-baseline assessment.

Table 4.  Overall incidence of abnormal vital signs (Safety population), n (%)

	QVA149			Indacaterol	Placebo
	600/100 μg	300/100 μg	150/100 μg	300 μg
	N = 49	N = 51	N = 51	N = 51	N = 53
Pulse rate –worst (minimum/maximum) post-baseline value
≤40 bpm	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
>40 –<90 bpm	32 (65.3)	36 (70.6)	34 (66.7)	36 (70.6)	33 (62.3)
≥90 bpm	17 (34.7)	15 (29.4)	17 (33.3)	15 (29.4)	20 (37.7)
Both ≤40 and ≥90 bpm	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Diastolic blood pressure –worst (minimum/maximum) post-baseline value
≤50 mmHg	4 (8.2)	1 (2.0)	3 (5.9)	1 (2.0)	3 (5.7)
>50 –<90 mmHg	24 (49.0)	31 (60.8)	25 (49.0)	27 (52.9)	26 (49.1)
≥90 mmHg	21 (42.9)	18 (35.3)	23 (45.1)	23 (45.1)	24 (45.3)
Both ≤50 and ≥90 mmHg	0 (0.0)	1 (2.0)	0 (0.0)	0 (0.0)	0 (0.0)
Systolic blood pressure –worst (minimum/maximum) post-baseline value
≤90 mmHg	2 (4.1)	1 (2.0)	1 (2.0)	0 (0.0)	1 (1.9)
>90 –<140 mmHg	13 (26.5)	22 (43.1)	20 (39.2)	18 (35.3)	19 (35.8)
≥140 mmHg	34 (69.4)	27 (52.9)	30 (58.8)	33 (64.7)	33 (62.3)
Both ≤90 and ≥140 mmHg	0 (0.0)	1 (2.0)	0 (0.0)	0 (0.0)	0 (0.0)

Baseline was defined as the measurement taken at 45 min prior to dosing on Day 1. The worst value post-baseline is one which is furthest from the mean of the upper and lower boundaries of the converted normal ranges.

Pulse rate: ≤40 bpm if at least one post-baseline value was ≤40 bpm but none ≥90 bpm; >40–<90 bpm if all post-baseline values were between 40 and 90 bpm; ≥90 bpm if at least one post-baseline value was ≥90 bpm but none ≤40 bpm; both ≤40 and ≥90 bpm if at least one post-baseline value was ≤40 bpm and also at least one value was ≥90 bpm.

Blood pressure: For overall post-baseline, subjects were counted in the ≤50 mmHg category if at least one post-baseline value was ≤50 mmHg but none ≥90 mmHg, subjects were counted in the 50–90 mmHg category if all post-baseline values were 50–90 mmHg, subjects were counted in the ≥90 mmHg category if at least one post-baseline value was ≥90 mmHg but none ≤50 mmHg, subjects were counted in the ‘Both ≤50 and ≥90 mmHg’ category if at least one post-baseline value was ≤50 mmHg and also at least one value was ≥90 mmHg.

Table 5.  Most common adverse events (occurring in >3% in any group) (Safety population), n (%)

	QVA149			Indacaterol	Placebo
	600/100 μg	300/100 μg	150/100 μg	300 μg
	N = 49	N = 51	N = 51	N = 51	N = 53
Any AE	14 (28.6)	13 (25.5)	17 (33.3)	10 (19.6)	12 (22.6)
Cough	3 (6.1)	2 (3.9)	3 (5.9)	2 (3.9)	1 (1.9)
Chronic obstructive pulmonary disease*	0 (0.0)	2 (3.9)	5 (9.8)	1 (2.0)	2 (3.8)
Pharyngitis	0 (0.0)	2 (3.9)	0 (0.0)	0 (0.0)	0 (0.0)
Headache	2 (4.1)	1 (2.0)	2 (3.9)	3 (5.9)	1 (1.9)
Dry mouth	3 (6.1)	1 (2.0)	3 (5.9)	0 (0.0)	0 (0.0)
Neck pain	2 (4.1)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Hypertension	0 (0.0)	3 (5.9)	1 (2.0)	1 (2.0)	1 (1.9)
Ventricular tachycardia	2 (4.1)	0 (0.0)	2 (3.9)	0 (0.0)	0 (0.0)

*Chronic obstructive pulmonary disease exacerbation.

Figure 3.  Trough FEV₁ (ITT population). Trough = average of 23 h 15 min and 23 h 45 min post-dose values. Data are LSM+SE. *p < 0.05 vs placebo, ^#p < 0.05 vs indacaterol 300 μg.