In addition to studies in adults, the efficacy and safety of tiotropium delivered via Respimat
® has been investigated in a large-scale clinical trial program in adolescents and children with asthma. Phase II, randomized, dose-ranging studies of tiotropium at 5, 2.5, and 1.25 μg in adolescents aged 12–17 years [
31] and children aged 6–11 years [
32] with symptomatic asthma despite maintenance treatment with at least ICS have demonstrated the efficacy and safety of tiotropium in these groups. Phase III clinical studies in adolescents (aged 12–17 years) [
33,
34] and children (aged 6–11 years) [
35,
36] with symptomatic moderate-to-severe asthma have been conducted to assess the efficacy and safety of once-daily tiotropium 5 and 2.5 µg vs. placebo as add-on therapy to treatment, including ICS (low-to-high dose) with or without additional controllers (Table
2). In each study, the primary endpoint was the change from baseline in peak FEV
1 within 3 h post-dose [FEV
1(0–3h)]. Secondary endpoints included trough FEV
1 response (change from baseline pre-dose FEV
1), the 7-question Asthma Control Questionnaire (ACQ-7) score, and the interviewer-administered Asthma Control Questionnaire (ACQ-IA) score in 6- to 11-year-old children. In addition, severe exacerbations were defined as asthma worsening that required treatment with systemic (including oral) corticosteroids for 3 consecutive days or more. Asthma worsening was defined as either a progressive increase in one or more asthma symptoms outside the patient’s usual range of day-to-day asthma (as determined by the study site investigator) and lasting for 2 or more consecutive days, or a decrease in the best morning PEF response of 30% or more of the mean morning response for 2 or more consecutive days.
Table 2
Overview of phase III studies with tiotropium Respimat® in adolescents and children
Adolescents (aged 12–17 years) |
RubaTinA-asthma ® (NCT01257230) [ 33] | Symptomatic moderate | 48 | At least ICS | Tio 5 µg, 134 Tio 2.5 µg, 125 Placebo, 138 |
PensieTinA-asthma ® (NCT01277523) [ 34] | Symptomatic severe | 12 | ICS + ≥ 1 controller | Tio 5 µg, 130 Tio 2.5 µg, 127 Placebo, 135 |
Children (aged 6–11 years) |
CanoTinA-asthma ® (NCT01634139) [ 35] | Symptomatic moderate | 48 | At least ICS | Tio 5 µg, 135 Tio 2.5 µg, 135 Placebo, 131 |
VivaTinA-asthma ® (NCT01634152) [ 36] | Symptomatic severe | 12 | ICS + ≥ 1 controller | Tio 5 µg, 130 Tio 2.5 µg, 136 Placebo, 134 |
Children (aged 1–5-years) |
NinoTinA-asthma ® (NCT01634113) [ 37] | Persistent asthmatic symptoms | 12 | At least ICS | Tio 5 µg, 31 Tio 2.5 µg, 36 Placebo, 34 |
3.2.1 Symptomatic Moderate Asthma
In the RubaTinA-asthma
® study, adolescents with symptomatic moderate asthma were randomized to receive tiotropium Respimat
® 5 or 2.5 μg, or placebo Respimat
® over 48 weeks as add-on therapy to ICS (200–800 μg of budesonide or equivalent in patients aged 12–14 years; 400–800 μg in patients aged 15–17 years) with or without an LTRA (Table
2) [
33]. Findings demonstrated that tiotropium add-on therapy improves lung function in adolescent patients with moderate asthma. Improvement in FEV
1(0–3h) after dosing at week 24 was statistically significant with both tiotropium doses compared with placebo: 5 μg of tiotropium, adjusted mean difference 174 mL [95% confidence interval (CI) 76–272;
p < 0.001]; 2.5 μg of tiotropium, 134 mL (95% CI 34–234;
p < 0.01). A statistically significant improvement in trough FEV
1 was observed for tiotropium 5 µg compared with placebo. At least one severe exacerbation was reported by two (1.5%), five (4.0%), and nine (6.5%) patients treated with tiotropium 5, 2.5 µg, and placebo, respectively. Considering asthma worsening, at least one episode was reported for 30 (22.4%), 34 (27.2%), and 37 (26.8%) patients receiving tiotropium 5, 2.5 µg, and placebo, respectively. ACQ-7 scores at week 24 were numerically lower (improved control) with tiotropium compared with placebo, but the differences were not significant.
The efficacy and safety of once-daily tiotropium as an add-on therapy in children (aged 6–11 years) with moderate persistent asthma on medium-dose ICS (200–400 µg/day) was investigated in the CanoTinA-asthma
® study over 48 weeks (Table
2) [
35,
40]. A significant improvement in FEV
1(0–3h) at week 24 was observed with both doses of tiotropium (5 and 2.5 µg), with adjusted mean differences of 164 mL (95% CI 103–225) and 170 mL (95% CI 108–231) vs. placebo, respectively (
p < 0.0001 for both comparisons). Statistically significant improvements were also seen in trough FEV
1 at week 24 for both doses (
p < 0.01). Severe asthma exacerbations and the number of patients reporting episodes of worsening occurred more frequently with placebo compared with tiotropium. Findings suggested that once-daily tiotropium as an add-on to maintenance therapy is safe and well tolerated in this patient group [
40].
A subsequent pooled analysis involving 798 adolescents (RubaTinA-asthma
®) [
33] and children (CanoTinA-asthma
®) [
35] with symptomatic moderate asthma reported similar findings to the adult studies [
41]. Statistically significant improvements in peak FEV
1(0–3h) responses vs. placebo at week 24 were observed for both doses of tiotropium (
p < 0.0001 for each comparison). The improvements observed in trough FEV
1 responses vs. placebo at week 24 for both tiotropium doses were also statistically significant (
p < 0.01 for each comparison). The differences were > 150 mL in peak FEV
1(0–3h) response and > 100 mL in trough FEV
1 response vs. placebo (Table
3). The significant improvements in peak FEV
1(0–3h) and trough FEV
1 responses were sustained at week 48. At least one asthma exacerbation (asthma worsening) was reported for 87 (32.3%) patients receiving tiotropium 5 µg, 97 (37.3%) patients receiving tiotropium 2.5 µg, and 103 (38.3%) patients receiving placebo during the 48-week treatment period. The ACQ-7 responder rates at week 24 were higher in the tiotropium groups than in the placebo group (tiotropium 5 μg, 81.0%; tiotropium 2.5 μg, 78.1%; placebo, 70.3%) (Table
3) [
41].
Table 3
Key efficacy findings from pooled phase III studies with tiotropium Respimat® 5 µg in adolescents and children with asthma
Symptomatic moderate asthma [ 41] |
RubaTinA-asthma® CanoTinA-asthma® | 269 | Peak FEV1 | 168 (109–228) < 0.0001 |
Trough FEV1 | 118 (53–182) 0.0004 |
Symptomatic severe asthma [ 43] |
VivaTinA-asthma® PensieTinA-asthma® | 258 | Peak FEV1 | 117 (51–183) 0.0005 |
Trough FEV1 | 71 (3–139) 0.04 |
FEF(25–75%) | 296 (168–425) < 0.0001 |
The safety and tolerability of tiotropium were also examined in the pooled population of adolescents and children with symptomatic moderate asthma, with an overall mean exposure of 330.6 ± 40.6 days to the study drug, with the majority of patients receiving at least 280 days of treatment. Adverse events were reported by 61.7, 63.5, and 63.6% of patients receiving tiotropium 5, 2.5 μg, and placebo, respectively. The proportion of patients with drug-related AEs was low (1.5, 0.4, and 1.1%, respectively). There were no AEs leading to discontinuation in the tiotropium groups and no deaths occurred. The most commonly reported AEs were asthma worsening, decreased PEF, and nasopharyngitis, of which asthma worsening was reported by more patients in the placebo group compared with tiotropium 5 and 2.5 μg (33.1, 25.7, and 29.2% of patients, respectively) (Table
4). Overall, similar to findings in adults, results from the pooled analysis demonstrate that the safety and tolerability of once-daily tiotropium as add-on to maintenance therapy were comparable to placebo [
42].
Table 4
Summary of safety outcomes from a pooled analysis of adolescents and children with symptomatic moderate asthma [
42]
Patients with any AE, n (%) | 166 (61.7) | 165 (63.5) | 171 (63.6) |
Patients with drug-related AEsa, n (%) | 4 (1.5) | 1 (0.4) | 3 (1.1) |
Patients with AEs leading to discontinuation, n (%) | 0 | 0 | 2 (0.7) |
Patients with serious AEs, n (%) | 4 (1.5) | 5 (1.9) | 8 (3.0) |
AEs in ≥ 2% of patients in any treatment arm, by preferred term |
Asthma worsening | 69 (25.7) | 76 (29.2) | 89 (33.1) |
Decreased PEF rate | 35 (13.0) | 40 (15.4) | 35 (13.0) |
Nasopharyngitis | 31 (11.5) | 28 (10.8) | 30 (11.2) |
Respiratory tract infection viral | 18 (6.7) | 19 (7.3) | 19 (7.1) |
Respiratory tract infection | 15 (5.6) | 16 (6.2) | 21 (7.8) |
Upper respiratory tract infection | 13 (4.8) | 5 (1.9) | 10 (3.7) |
Headache | 11 (4.1) | 12 (4.6) | 4 (1.5) |
Rhinitis allergic | 9 (3.3) | 7 (2.7) | 11 (4.1) |
Viral infection | 9 (3.3) | 7 (2.7) | 6 (2.2) |
Rhinitis | 8 (3.0) | 11 (4.2) | 10 (3.7) |
Pharyngitis | 6 (2.2) | 9 (3.5) | 9 (3.3) |
Bronchitis | 5 (1.9) | 9 (3.5) | 3 (1.1) |
Tonsillitis | 4 (1.5) | 6 (2.3) | 10 (3.7) |
Sinusitis | 4 (1.5) | 7 (2.7) | 3 (1.1) |
Cough | 2 (0.7) | 6 (2.3) | 5 (1.9) |
3.2.2 Symptomatic Severe Asthma
In PensieTinA-asthma
®, adolescent patients were randomized to receive tiotropium 5 or 2.5 μg, or placebo over 12 weeks as either add-on to high-dose ICS (> 400 μg of budesonide or equivalent in patients aged 12–14 years; 800–1600 μg in patients aged 15–17 years) plus one or more controllers (e.g., LABA and/or LTRA), or as add-on to medium-dose ICS (200–400 μg of budesonide or equivalent in patients aged 12–14 years; 400–800 μg in patients aged 15–17 years) plus two or more controllers (e.g., LABA, LTRA, or sustained-release theophylline) (Table
2) [
34]. In this study, tiotropium 5 µg provided numerical improvements in peak FEV
1(0–3h) compared with placebo [90 mL (95% CI − 19 to 198;
p = 0.104)]. There was a statistically significant improvement in peak FEV
1(0–3h) response with the 2.5-µg dose [111 mL (95% CI 2–220;
p = 0.046)], but because the efficacy of tiotropium 5 µg over placebo could not be demonstrated, and thus the primary endpoint of the trial was not met, all further treatment comparisons were considered descriptive only, to control the type I error [
34]. Numerical improvements in trough FEV
1 response at week 12 were observed with both tiotropium 5 µg [54 mL (95% CI − 61 to 168;
p = 0.361)] and tiotropium 2.5 µg [115 mL (95% CI 0–231;
p = 0.051)] compared with placebo. The lack of statistical significance observed with these data was somewhat unexpected in view of all other investigations of tiotropium as add-on to at least ICS therapy in adolescents [
33] and adults [
27,
29] with asthma, which have demonstrated that the 5-µg dose provides statistically significant improvements in both peak and trough FEV
1.
With no minimal clinically important difference in lung function improvements established in pediatric patients, it is difficult to interpret the clinical relevance of non-significant changes. However, lung function improvements are broadly of the same magnitude in adolescents and children as previously reported in adults. The incidence of both severe exacerbations and episodes of asthma worsening were low, and the safety and tolerability of tiotropium were comparable to placebo. One patient in each of the tiotropium 2.5-µg and placebo treatment groups and two patients receiving tiotropium 5 µg experienced a severe asthma exacerbation during the study. At least one episode of asthma worsening was reported for 15 (11.5%), 18 (14.2%), and 25 (18.5%) patients receiving tiotropium 5, 2.5 µg, and placebo, respectively. The ACQ-7 scores at week 12 were comparable for both tiotropium doses and were not significantly different to findings with placebo.
The VivaTinA-asthma
® study was the first phase III study of tiotropium in children (aged 6–11 years) with symptomatic severe disease. Over a 12-week period, the efficacy and safety of tiotropium added on to high-dose ICS (> 400 µg/day) with one or more controller medication or medium-dose ICS (200–400 µg/day) with two or more controller medications in symptomatic severe asthma were assessed [
36]. Compared with placebo, tiotropium 5 μg add-on therapy significantly improved the primary endpoint, peak FEV
1(0–3h) [139 mL (95% CI 75–203;
p < 0.001)]. Similarly, a significant difference was observed in improvements in trough FEV
1 response vs. placebo for the 5-µg dose. No significant differences in adjusted mean peak forced vital capacity (FVC) within 3 h post-dose [FVC
(0–3h)] or trough FVC responses were observed with either dose of tiotropium.
The safety and tolerability of tiotropium were comparable to placebo. A severe exacerbation was experienced by seven (5.4%), three (2.2%), and eight (6.0%) participants being treated with tiotropium 5, 2.5 µg, or placebo, respectively. At least one episode of asthma worsening was reported for 26.9, 21.3, and 35.1% of those receiving tiotropium 5, 2.5 µg, or placebo, respectively. The risk of severe asthma exacerbations and episodes of asthma worsening was lower with tiotropium than with placebo, a difference that reached statistical significance for episodes of asthma worsening with tiotropium 2.5 µg vs. placebo (
p = 0.006). Changes in ACQ-IA scores were similar between tiotropium and placebo, with over 75% of participants in each group showing a response (improvement of at least 0.5). In addition, there was no difference in improvement in the adjusted mean number of asthma symptom-free days with both doses of tiotropium compared with placebo. Once-daily tiotropium was also well tolerated as an add-on therapy to ICS with other maintenance therapies in children with symptomatic severe asthma [
36].
In the pooled analysis of these data, it was shown that in patients aged 6–17 years with symptomatic severe asthma (
n = 792), either dose of tiotropium added on to ICS significantly improved measures of lung function (Table
3) [
43]. Peak FEV
1(0–3h) response at week 12 was significantly improved with both the 5 and 2.5-μg dose of tiotropium vs. placebo; the adjusted difference vs. placebo was 117 mL (95% CI 51–183;
p = 0.0005) and 74 mL (95% CI 8–140;
p = 0.027), respectively. Improvements in forced expiratory flow between 25 and 75% of vital capacity response, more closely representing changes in the lower airways, and the FEV
1/FVC ratio, as the pivotal marker of obstructive lung disease, were also reported. Only the 5-μg dose of tiotropium significantly improved trough FEV
1 compared with placebo [
43]. While findings from the pooled analysis demonstrate significant improvements in peak FEV
1(0–3h) response compared with placebo, it must be acknowledged that this primary endpoint was not met in PensieTinA-asthma
®, which was conducted solely in adolescents.
As discussed later, studies in children and adolescents present challenges; poor adherence, a common problem in asthma management, may in part explain these findings, in addition to the short study duration (12 weeks) and the strong placebo effect observed, pointing towards a possible low treatment adherence prior to inclusion [
34]. While the pooled analysis involves a large number of patients across a wide age range, the limitations of these types of analyses must also be acknowledged. Regarding safety, the most common AEs, with an incidence > 2% in any treatment group in either study, were asthma, decreased PEF rate, and nasopharyngitis (Table
5) [
43]. Overall, this pooled analysis confirms that the addition of tiotropium to existing controller medication improves lung function in children and adolescents with symptomatic severe asthma.
Table 5
Summary of safety outcomes from a pooled analysis of adolescents and children with symptomatic severe asthma [
43]
Patients with any AE, n (%) | 99 (38.1) | 101 (38.4) | 114 (42.4) |
Patients with drug-related AEsa, n (%) | 1 (0.4) | 0 | 3 (1.1) |
Patients with AEs leading to discontinuation, n (%) | 2 (0.8) | 0 | 3 (1.1) |
Patients with serious AEs, n (%) | 6 (2.3) | 3 (1.1) | 2 (0.7) |
AEs in > 2% of patients in any treatment arm, by preferred term |
Asthma | 39 (15.0) | 34 (12.9) | 44 (16.4) |
Decreased PEF rate | 20 (7.7) | 24 (9.1) | 33 (12.3) |
Nasopharyngitis | 11 (4.2) | 11 (4.2) | 14 (5.2) |
Viral respiratory tract infection viral | 6 (2.3) | 2 (0.8) | 7 (2.6) |
Respiratory tract infection | 4 (1.5) | 1 (0.4) | 7 (2.6) |
Rhinitis | 2 (0.8) | 3 (1.1) | 8 (3.0) |
Upper respiratory tract infection | 4 (1.5) | 3 (1.1) | 4 (1.5) |
Observations of improvements in lung function with tiotropium add-on therapy in children and adolescents with symptomatic moderate or severe asthma are consistent with findings in adults with symptomatic asthma [
26,
27,
29]. However, the dose response observed in children and adolescents with symptomatic moderate asthma was not observed to the same extent in patients with severe disease [
34]. Furthermore, improvements in asthma control were observed across age groups and asthma severities in all treatment groups, including placebo. However, the studies were not statistically powered to assess asthma symptom scores. It must be acknowledged that short study durations in children and adolescents with symptomatic severe asthma do not allow for a comprehensive assessment of asthma control and exacerbations. In all the studies reported here, the frequency of severe exacerbations in children and adolescents were low and did not allow for the calculation of any treatment effect. The published evidence, however, demonstrates that tiotropium is a safe and well-tolerated treatment.
In addition to the studies reported here, a further analysis of the safety and tolerability of once-daily tiotropium add-on therapy was assessed in a pooled analysis using data from > 1600 patients aged 1–17 years with symptomatic asthma of different severities. Safety findings were comparable to placebo regardless of age group and asthma severity. This finding is of particular importance for children, where safety is the major consideration prior to the incorporation of new treatment strategies [
44].