A Randomised Dose-ranging Study of Tiotropium Respimat® in Children With Symptomatic Asthma Despite Inhaled Corticosteroids

Christian Vogelberg; Petra Moroni-Zentgraf; Migle Leonaviciute-Klimantaviciene; Ralf Sigmund; Eckard Hamelmann; Michael Engel; Stanley Szefler

Disclosures

Respiratory Research. 2015;16(20) 

In This Article

Results

In total, 101 patients were randomised to receive study treatment. Seventy-six patients received tiotropium Respimat® 5 μg, 74 received tiotropium Respimat® 2.5 μg, 75 received tiotropium Respimat® 1.25 μg and 76 received placebo Respimat® (Additional file 1: Figure S1 http://respiratory-research.com/content/16/1/20/additional). One hundred patients completed all three treatment periods, with one patient discontinuing from the study prematurely (consent withdrawn for non-AE-related reasons during the first 4-week treatment period while receiving tiotropium Respimat® 5 μg); this patient was excluded from the full analysis set.

Baseline Demographics and Disease Characteristics

Most patients were male (68.3%), with a mean age of 8.8 years and a mean duration of asthma of 4.5 years (Table 1). Only 5.9% of patients had been exposed to household/second-hand smoking. Approximately two-thirds of patients had concomitant diseases at screening (63.4%), the most common being allergic rhinitis (53.5%).

During the 3 months prior to screening, all patients received treatment with ICS and 36.6% were also treated with a LABA, while 45.5% had taken additional leukotriene modifiers. At the time of randomisation (Visit 2), all patients were taking ICS, with 45.5% of patients also receiving leukotriene modifiers. LABAs were not permitted during the run-in or treatment periods.

Patients' baseline asthma characteristics are summarised in Table 2. At screening, mean pre- and post-bronchodilator FEV1 values (± standard deviation: 1.539 ± 0.385 L, 1.909 ± 0.469 L) were 79.7% and 98.9% of predicted normal, respectively. Mean reversibility with bronchodilator use (% of pre-bronchodilator) was 370 ± 171 mL (24.6%). At baseline, mean FEV1 was 1.640 ± 0.386 L (85.4% of predicted normal), with 29.7% of patients having an FEV1 value >90% of predicted normal.

Efficacy

For the primary efficacy end point, statistically significant differences in peak FEV1(0–3h) response after 4 weeks of treatment were observed for each tiotropium Respimat® dose group versus placebo Respimat® (Figure 2). The adjusted mean differences between tiotropium Respimat® 5 μg, 2.5 μg and 1.25 μg versus placebo Respimat® were 87 mL (p = 0.0002), 104 mL (p < 0.0001) and 75 mL (p = 0.0011), respectively. There was no dose-dependent response observed in patients treated with tiotropium Respimat®, with only minor, non-statistically significant differences between the different doses in peak FEV1(0–3h) response after 4 weeks of treatment.

Figure 2.

Peak FEV 1(0–3h) and trough FEV 1 responses after 4 weeks of treatment (full analysis set). Adjusted for 'treatment', 'period', 'patient' and 'baseline'. *p < 0.05; ***p < 0.001 versus placebo Respimat®. FEV1, forced expiratory volume in 1 second; peak FEV1(0–3h), peak forced expiratory volume in 1 second within 3 hours post-dosing.

Tiotropium Respimat® also improved secondary and additional efficacy end points, including trough FEV1 response, FEV1 AUC(0–3h) response and FEV1 response over 3 hours post-dosing. A statistically significant difference in adjusted mean trough FEV1 response was observed for each tiotropium Respimat® dose group versus placebo Respimat® (Figure 2): 5 μg = 98 mL (p < 0.0001), 2.5 μg = 105 mL (p < 0.0001) and 1.25 μg = 75 mL (p = 0.0023). A statistically significant difference in adjusted mean FEV1 AUC(0–3h) response was also observed for each tiotropium Respimat® dose group versus placebo Respimat® (Figure 3): 5 μg = 91 mL (p < 0.0001), 2.5 μg = 99 mL (p < 0.0001) and 1.25 μg = 68 mL (p = 0.0013). The FEV1 responses with all doses of tiotropium Respimat® were significantly superior to those with placebo Respimat® at all time points up to 3 hours post-dosing (Figure 4).

Figure 3.

FEV 1 AUC (0–3h) response after 4 weeks of treatment (full analysis set). Adjusted for 'treatment', 'period', 'patient' and 'baseline'. *p < 0.05; ***p < 0.001 versus placebo Respimat®. AUC(0–3h), area under the curve within 3 hours post-dosing; FEV1, forced expiratory volume in 1 second.

Figure 4.

FEV 1 response over 3 hours post-dosing (full analysis set). FEV1, forced expiratory volume in 1 second.

Although peak FVC(0–3h), trough FVC and FVC AUC(0–3h) responses were improved on tiotropium Respimat® therapy, the improvements were statistically significant only for FVC AUC(0–3h) response with the 2.5 μg dose (p = 0.0383).

Increases from baseline in morning and evening PEF responses were seen after 4 weeks for all tiotropium Respimat® dose groups. A statistically significant improvement in adjusted mean morning PEF response was observed for all three tiotropium Respimat® doses (5 μg = 16 L/min [p = 0.0036], 2.5 μg = 13 L/min [p = 0.0215] and 1.25 μg = 15 L/min [p = 0.0061]), with a statistically significant improvement in adjusted mean evening PEF response of 17 L/min (p = 0.0024) also observed for the 5 μg dose, when compared with placebo Respimat® (Figure 5).

Figure 5.

Morning and evening PEF response after 4 weeks of treatment (full analysis set). Adjusted for 'treatment', 'period', 'patient' and 'baseline'. *p < 0.05 versus placebo Respimat®. PEF, peak expiratory flow.

Statistically significant improvements in adjusted mean forced expiratory flow 25–75% response were observed at all time points up to 3 hours post-dosing for all tiotropium Respimat® dose groups versus placebo Respimat®: 5 μg = 318 mL/sec, 2.5 μg = 319 mL/sec and 1.25 μg = 296 mL/sec at 3 hours post-dosing (all p < 0.0001). No dose-dependent response was observed, and there were no significant differences between the three tiotropium Respimat® dose groups.

Although not statistically significant, numerical improvements in asthma control and quality of life were observed following treatment with tiotropium Respimat®, compared with placebo Respimat® (ACQ-7 adjusted mean response: 5 μg = −0.088, 2.5 μg = −0.120 and 1.25 μg = −0.057; total PAQLQ[S] adjusted mean response: 5 μg = 0.091, 2.5 μg = 0.029 and 1.25 μg = 0.024).

Safety and Tolerability

The incidence of AEs experienced while receiving study treatment was comparable across the three tiotropium Respimat® dose groups and the placebo Respimat® treatment group, with events reported for approximately 10% of patients in each group (Table 3). No deaths, serious AEs, AEs leading to discontinuation of study medication, drug-related AEs or pre-specified significant AEs were reported during the study. Only one patient prematurely discontinued study medication, due to consent withdrawal for non-AE-related reasons. All other types of AE were reported in less than 3% of patients and no individual AE was reported in more than two patients in any treatment group.

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