Long-term safety of tiotropium/olodaterol Respimat^® in patients with moderate-to-very severe COPD and renal impairment in the TONADO^® studies

Figures & data

Table 1 Renal impairment categories

Impairment	Estimated CLcr (mL/min)
Normal	≥90
Mild	60–89
Moderate	30–59
Severe	15–29
End-stage diseasea	<15 (not on dialysis) or requiring dialysis

Note:

a Not observed in the TONADO^® studies due to the inclusion criteria.⁷

Abbreviation: CLcr, creatinine clearance (determined using the Cockcroft–Gault formula).

Table 2 Demographic and baseline patient characteristics by renal impairment category

	Olodaterol 5 μg (n=1,018)a			Tiotropium 5 μg (n=1,021)			Tiotropium/olodaterol 5/5 μg (n=1,002)b
	Renal impairmentc			Renal impairmentc			Renal impairmentc
	Normal	Mild	Moderate	Normal	Mild	Moderate	Normal	Mild	Moderate
Treated patients, n (%)	433 (42.5)	449 (44.1)	134 (13.2)	455 (44.6)	434 (42.5)	132 (12.9)	411 (41.0)	450 (44.9)	138 (13.8)
Male, n (%)	321 (74.1)	322 (71.7)	104 (77.6)	332 (73.0)	315 (72.6)	99 (75.0)	286 (69.6)	326 (72.4)	97 (70.3)
Age, years	60.5±7.4	65.3±7.2	72.1±6.7	59.5±7.5	65.7±7.4	72.7±6.7	59.7±7.6	65.2±7.4	71.3±6.1
BMI, kg/m^2	29.1±6.2	23.8±3.9	22.3±3.6	28.6±5.5	24.3±4.0	22.5±3.8	29.3±5.2	23.9±4.0	22.1±4.2
Smoking history
Pack years	46.3±24.5	45.5±24.0	71.0±53.0	45.2±26.5	46.7±27.2	72.0±54.5	46.0±24.7	46.1±22.9	64±46.4
GOLD stage, n (%)
GOLD 2	227 (52.4)	223 (49.7)	12 (9.0)	228 (50.1)	210 (48.4)	14 (10.6)	202 (49.1)	218 (48.4)	12 (8.7)
GOLD 3	155 (35.8)	164 (36.5)	–	176 (38.7)	164 (37.8)	–	156 (38.0)	182 (40.4)	–
GOLD 4	51 (11.8)	62 (13.8)	53.6 (28.6)	50 (11.0)	60 (13.8)	49.3 (32.9)	53 (12.9)	50 (11.1)	48.6 (26.9)
Study exposure, days	327±96.1	326±96.8	322±99.5	333±91.2	330±92.9	336±85.6	344±74.7	337±83.2	341±76.0
Cardiovascular medication, n (%)	275 (63.5)	244 (54.3)	86 (64.2)	263 (57.8)	242 (55.8)	85 (64.4)	254 (61.8)	228 (50.7)	80 (58.0)
Pulmonary medication, n (%)	339 (78.3)	366 (81.5)	114 (85.1)	335 (73.6)	352 (81.1)	103 (78.0)	328 (79.8)	347 (77.1)	119 (86.2)

Notes:

a Includes 2 patients with severe renal impairment.

b Includes 3 patients with severe renal impairment.

c Table 1. Defined using Cockcroft–Gault formula. Data are mean ± standard deviation unless otherwise stated.

Abbreviations: BMI, body mass index; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

Figure 1 Baseline comorbidity by renal impairment category.

Table 3 Summary of adverse events by baseline renal impairment

Patients, n (%)	Olodaterol 5 μg (n=1,018)a			Tiotropium 5 μg (n=1,021)			Tiotropium/olodaterol 5/5 μg (n=1,002)b			Total (n=3,041)c
	Renal impairmentd			Renal impairmentd			Renal impairmentd			Renal impairmentd
	Normal	Mild	Moderate	Normal	Mild	Moderate	Normal	Mild	Moderate	Normal	Mild	Moderate
Total treated	433 (100)	449 (100)	134 (100)	455 (100)	434 (100)	132 (100)	411 (100)	450 (100)	138 (100)	1,299 (100)	1,333 (100)	404 (100)
Any AE	325 (75.1)	340 (75.7)	113 (84.3)	322 (70.8)	321 (74.0)	105 (79.5)	296 (72.0)	330 (73.3)	110 (79.7)	943 (72.6)	991 (74.3)	318 (78.7)
Severe AE	75 (17.3)	55 (12.2)	29 (21.6)	58 (12.7)	70 (16.1)	16 (12.1)	51 (12.4)	72 (16.0)	29 (21.0)	184 (14.2)	197 (14.8)	74 (18.3)
Related AE (defined by the investigator)e	31 (7.2)	29 (6.5)	9 (6.7)	20 (4.4)	30 (6.9)	12 (9.1)	22 (5.4)	33 (7.3)	15 (10.9)	73 (5.6)	92 (6.9)	36 (8.9)
Other significant AEf	18 (4.2)	20 (4.5)	8 (6.0)	16 (3.5)	23 (5.3)	7 (5.3)	8 (1.9)	18 (4.0)	5 (3.6)	42 (3.2)	61 (4.6)	20 (5.0)
AEs leading to study drug discontinuation	39 (9.0)	43 (9.6)	20 (14.9)	35 (7.7)	43 (9.9)	12 (9.1)	19 (4.6)	40 (8.9)	16 (11.6)	93 (7.2)	126 (9.5)	48 (11.9)
Serious AEs	79 (18.2)	62 (13.8)	35 (26.1)	62 (13.6)	81 (18.7)	26 (19.7)	58 (14.1)	75 (16.7)	32 (23.2)	199 (15.3)	218 (16.4)	93 (23.0)
Fatal	3 (0.7)	5 (1.1)	6 (4.5)	5 (1.1)	10 (2.3)	2 (1.5)	6 (1.5)	9 (2.0)	3 (2.2)	14 (1.1)	24 (1.8)	11 (2.7)
Life threatening	1 (0.2)	1 (0.2)	1 (0.7)	1 (0.2)	1 (0.2)	0 (0.0)	3 (0.7)	2 (0.4)	0 (0.0)	5 (0.4)	4 (0.3)	1 (0.2)
Disability	1 (0.2)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.2)	1 (0.8)	1 (0.2)	2 (0.4)	0 (0.0)	2 (0.2)	3 (0.2)	1 (0.2)
Requires hospitalization	69 (15.9)	58 (12.9)	30 (22.4)	61 (13.4)	70 (16.1)	22 (16.7)	53 (12.9)	68 (15.1)	28 (20.3)	183 (14.1)	196 (14.7)	80 (19.8)
Prolonged hospitalization	5 (1.2)	4 (0.9)	3 (2.2)	2 (0.4)	1 (0.2)	0 (0.0)	1 (0.2)	3 (0.7)	2 (1.4)	8 (0.6)	8 (0.6)	5 (1.2)
Other	10 (2.3)	7 (1.6)	3 (2.2)	1 (0.2)	12 (2.8)	4 (3.0)	5 (1.2)	5 (1.1)	2 (1.4)	16 (1.2)	24 (1.8)	9 (2.2)

Notes:

a Includes 2 patients with severe renal impairment.

b Includes 3 patients with severe renal impairment.

c Includes 5 patients with severe renal impairment.

d Table 1. Defined using Cockcroft–Gault formula.

e Reported by the investigator with a reasonable possibility of being drug-related.

f Based on the ICH E3 guideline, non-serious AEs leading to discontinuation or dose reduction of study drug were lassified as “other significant” AEs. A patient may be counted in >1 seriousness criterion. Percentages were calculated using the total number of patients per treatment as the denominator. MedDRA (version 16.1) used for AE reporting.

Abbreviations: AE, adverse event; ICH, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; MedDRA, Medical Dictionary for Regulatory Activities.

Figure 2 Incidence of adverse events and serious adverse events by renal impairment category.

Notes: (A) Patients with any AE. (B) Patients with SAEs. (C) Fatal SAEs.
Abbreviations: AE, adverse event; Olo, olodaterol; SAE, serious AE; Tio, tiotropium.

Figure 3 Discontinuation of study medication by renal impairment category.

Notes: (A) Prematurely discontinued from trial medication. (B) Discontinued due to adverse event.
Abbreviations: Olo, olodaterol; Tio, tiotropium.

Table 4 Adverse events in individual patients with severe renal impairment at baseline

Treatment group	Age	Sex	Event (LLT)a	Relatedb	Serious
Olodaterol 5 μg	70	M	None reported	–	–
	79	M	Cellulitis of leg	N	N
			Bronchopneumonia, COPD exacerbation	N	N
			Cellulitis of oral soft tissues	N	N
			Chest tightness	N	N
			Epigastric pain	N	N
Tiotropium 5 μg	–	–	None reported	–	–
Tiotropium/olodaterol 5/5 μg	80	M	Chest pain (at screening before randomization–no study medication received)	N	N
			Upper respiratory tract infection	N	N
			Bronchitis, COPD exacerbation	N	N
	80	F	Urinary infection	N	N
			Upper respiratory tract infection	N	N
			Headache	N	N
	76	M	Dysgeusia, insomnia, sudoresis, tremor	Y	N

Notes:

a After start of randomized study medication.

b Reported by the investigator with a reasonable possibility of being drug-related.

Abbreviations: F, female; LLT, Medical Dictionary for Regulatory Activities Low Level Term; M, male; N, no; Y, yes.

Figure 4 Exposure-adjusted incidence rate ratios and 95% CI (forest plots) of clinically relevant adverse event groups associated with renal impairment comparing tiotropium/olodaterol with the monocomponents.

Note: ^aTreatment exposure time adjusted.
Abbreviations: MACE, major adverse cardiovascular event; Olo, olodaterol; Tio, tiotropium.

Figure S1 Exposure-adjusted incidence rate ratios and 95% confidence intervals (forest plots) of clinically relevant adverse event groups associated with renal impairment comparing tio/olo with the monocomponents.

Notes: (A) Cardiovascular events. (B) Respiratory events. (C) Urinary tract events. (D) Potential anticholinergic events. ^aTreatment exposure time adjusted.

Abbreviations: MACE, major adverse cardiovascular event; Olo, olodaterol; Tio, tiotropium.

BuhlRMaltaisFAbrahamsRTiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4)Eur Respir J201545496997925573406

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