Combination of Formoterol and Tiotropium in the Treatment of COPD: Effects on Lung Function

Figures & data

Table 1 Functional effect of combining single doses of formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
Cazzola et al., 2004 ([42])	F 12 μg,; T 18 μg; F 12 μg + T 18 μg with washout period between the test days of at least 96 h.	20 stable outpatients. (mean baseline FEV1:34.8% ± 13.2 predicted).	Double-blind, double-dummy, cross-over, randomized trial.	Rate of onset of action; maximum response; time course of bronchodilating effect over 24 h; FEV1 AUC over 12 and 24 h	Significantly faster onset of action and a trend for a greater maximum bronchodilation with F, alone or in combination with T, than with T alone. At 24 h, mean FEV1 significantly higher than pre-dosing value following T and F +T, but differences between treatments not significant. Mean FEV1 AUC0-12 h and FEV1 AUC0-24 h after F + T higher than, but not statistically significantly different from, that of T or F alone.
Brashier et al., 2005 ([43])	T 18 μg; F 12 μg + T 18 μg in a single inhaler.	23 stable patients (mean baseline FEV1: 40.6% ± 14.1 predicted).	Double-blind, cross-over, randomized trial.	Changes in FEV1 and FVC over 24 h.	Better FEV1 and FVC responses with F + T in a single inhaler than T alone over 24 h.
Cazzola et al., 2005 ([44])	T 18 μg q.d., or F 12 μg b.i.d. over a 5-day period for each drug, with a 10-day washout in between. At the end of each period, patients inhaled both drugs separated by 180 min in alternate sequence.	20 stable outpatients (mean baseline FEV1: 1.13 L (95% CI: 0.96–1.32) for T and 1.13L (95% CI: 0.94–1.33) for F.	Randomized, crossover trial.	Changes in FEV1 and FVC AUC over 6 h.	Significant improvement in pulmonary function adding T or F in patients already under regular treatment with F or T, respectively, with no statistically significant difference between the different sequences.
Di Marco et al., 2006 ([45])	F 12 μg; T 18 μg; F 12 μg + T 18 μg in randomized sequence on days 1, 3 and 5.	21 patients with a mild to moderate AECOPD (mean FEV1: 38 ± 14% predicted).	Double-blind, double-dummy, cross-over, randomized trial.	Changes in FEV1, FVC and IC AUC over 12 and 24 h; time course of bronchodilating effect; maximum response	Mean FEV1, FVC and IC AUC0 - 12 h and AUC0 - 24 h after F + T significantly larger than F and T alone; differences between F and T not statistically significant Significantly faster onset of action, and a greater maximum bronchodilation with F + T, than with T or F alone.

F: formoterol; T: tiotropium; AUC: area under the curve; AECOPD: acute exacerbation of COPD.

Table 2 Functional effect of regular treatment with formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
van Noord et al. 2005 ([47])	T 18 μg OD; F 12 μg BID or F 12 μg + T 18 μg OD for three 6-week periods.	71 patients (mean FEV1: 37.2± 8.6 predicted).	Randomised, double-blind, three-way, crossover trial.	24-h FEV1, and FVC at the end of each treatment; rescue salbutamol.	Significant improvements FEV1 and FVC with T being superior to F during the daytime (0–12 h), but bronchodilator effects with F + T ODsuperior to single-agent therapy during the daytime (0–12 h) and the night-time (12–24 h). Daytime salbutamol use significantly lower during combination therapy.
van Noord et al. 2006 ([49])	2-week treatment periods of T alone; T + F OD or BID following a 2-week pretreatment period with T.	95 patients with stable COPD (mean FEV1: 38 ± 10 predicted).	Randomized, open-label, placebo-controlled, three-way crossover trial.	Changes in FEV1, FVC- and IC AUC over 0–24 h and 12–24 h; rescue salbutamol.	Combination of T OD with F BID the most effective. Compared with T alone, add-on F in the morning produced improvement in FEV1, FVC, and IC for > 12 h. The second add-on dose of F in the evening caused further improvement in FEV1 for 12 h, but in FVC and IC for < 12 h. Compared with T alone, add-on F OD and BID reduced the use of rescue salbutamol during the daytime and with add-on F BID also during the nighttime.
Tashkin et al. (in press) ([50])	F 12 μg BID + T 18 μg OD or T 18 μg OD + P for 12 weeks.	240 patients with stable COPD	Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial.	Normalized FEV1 AUC over 0–4h at the last visit; trough effects on FEV1 and FVC (average of values 10 and 30 minutes predose); onset of effects on FEV1 following the first dose rescue salbutamol.	Significant increase in the normalized FEV1 AUC0 − 4h after F + T compared with T. At endpoint, increases from baseline in trough FEV1 and FVC significantly greater with F + T than with T. The increase in FEV1 5 minutes postdose was significantly greater with F + T than with T. Use of salbutamol decreased in both treatment groups, but reduction in daytime use significantly greater with F + T than with T.
Vogelmeier et al. 2008 ([51])	F10 μg BID via MDDPI; placebo BID via MDDPI; T18 μg OD via the HandiHaler® + F 10 μg BID via MDDPI; T 18 μg OD via the HandiHaler® + placebo BID via MDDPI.	847 patients (mean FEV1 52% predicted)	Multicenter double-blind for treatment with MDDPI, but not for other comparisons (T administered open-label). Randomization not stratified.	FEV1 measured 2 h post-dose after 24 weeks of treatment. FEV1 and FVC at other time points during the study; COPD exacerbations; symptom scores, rescue medication use and PEF; quality of life; 6-minute walking distance.	FEV1 2 h post-dose after 24 weeks: all three treatments superior to placebo, differences in favour of F + T versus F or T. F + T statistically superior to monotherapy for: FEV1 2 h post-dose after 24 weeks vs. F; FEV1 5 min after the first dose and at 12 weeks vs. T; and PEF averaged over the first 6 weeks vs. both. The three active treatments were significantly more effective than placebo for other endpoints.

F: formoterol; T: tiotropium; AUC: area under the curve; MDDPI: multi-dose dry powder inhaler; P: placebo; OD: once daily; BID: bis in die.

Table 3 Concomitant treatment with nebulized formoterol and tiotropium

Author	Treatment arms	Number of subjects	Trial design	Key endpoints	Major results
Tashkin et al., 2008 ([60])	FFIS 20 μg BID + T OD via the HandiHaler® or nebulized P BID + T OD via the HandiHaler® for 6 weeks	129 patients (mean FEV1 38.4 ± 10.4 predicted)	Randomized, double-blind (only with FFIS and placebo), placebo-controlled, parallel group trial	FEV1 AUC0-3 h; TDI; SGRQ.	Significant improvements in FEV1 AUC0−3, peak FEV1, and trough FVC for FFIS + T vs. T alone maintained throughout the 6 week-treatment. Statistically significant improvements in TDI for FFIS + T vs. T alone. SGRQ not significantly impacted by FFIS + T vs. T alone.

FFIS: formoterol fumarate inhalation solution;T: tiotropium; P: placebo; OD: once daily; BID: bis in die; TDI: transition dyspnea index; SGRQ: St. George's Respiratory Questionnaire.

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