TABLE 1

Overview of study designs and key inclusion/exclusion criteria

NinoTinA-asthma [23]CanoTinA-asthma [21]VivaTinA-asthma [20]RubaTinA-asthma [17]PensieTinA-asthma [18]
ClinicalTrials.gov identifierNCT01634113NCT01634139NCT01634152NCT01257230NCT01277523
Phase and design#Phase 2/3Phase 3, randomised, double-blind, placebo-controlled, parallel-groupPhase 3, randomised, double-blind, placebo-controlled, parallel-groupPhase 3, randomised, double-blind, placebo-controlled, parallel-groupPhase 3, randomised, double-blind, placebo-controlled, parallel-group
ObjectivesEfficacy and safetyEfficacy and safetyEfficacy and safetyEfficacy and safetyEfficacy and safety
Patient population1–5-year-olds with persistent asthmatic symptoms6–11-year-olds with symptomatic moderate asthma6–11-year-olds with symptomatic severe asthma12–17-year-olds with symptomatic moderate asthma12–17-year-olds with symptomatic severe asthma
History of asthmaNA≥6 months≥6 months≥3 months≥3 months
Symptomatic asthmaDaytime symptoms more than twice a week; any limitation of activities; any nocturnal symptoms/awakenings; need for rescue medication >2 days·week−1ACQ-IA ≥1.5ACQ-IA ≥1.5ACQ ≥1.5ACQ ≥1.5
Minimum asthma controller medicationStable ICS, with or without another controller, for ≥4 weeks before screeningMedium-dose ICS (200–400 μg·day−1 budesonide or equivalent dose), with or without another controller, for ≥4 weeks before screening; LABA had to be discontinued ≥24 h prior to screeningHigh-dose ICS (>400 μg·day−1 budesonide or equivalent dose) plus ≥1 controller or medium-dose ICS (200–400 μg·day−1 budesonide or equivalent dose) plus ≥2 controllers for ≥4 weeks before screeningMedium-dose ICS (400–800 μg·day−1 budesonide or equivalent dose), with or without LTRA, for ≥4 weeks before screening; LABA had to be discontinued ≥72 h prior to screeningHigh-dose ICS (800–1600 μg·day−1 budesonide or equivalent dose) plus ≥1 controller or medium-dose ICS (400–800 μg·day−1 budesonide or equivalent dose) plus ≥2 controllers for ≥4 weeks before screening
Pre-bronchodilator FEV1 % pred at screening≤90% for 5-year-olds60–90%60–90%60–90%60–90%
FEV1 reversibility at screening≥12%, 15–30 min after 200 μg salbutamol≥12%, 15–30 min after 200 μg salbutamol≥12% and ≥200 mL, 15–30 min after 400 μg salbutamol (age >14 years) or ≥12% only (age 12–14 years)≥12% and ≥200 mL, 15–30 min after 400 μg salbutamol (age >14 years) or ≥12% only (age 12–14 years)
Variability of absolute FEV1 from screening to randomisation±30%±30%±30%±30%
Smoking historyNonsmoker or ex-smoker who stopped smoking ≥1 year prior to enrolmentNonsmoker or ex-smoker who stopped smoking ≥1 year prior to enrolment
Exclusion criteriaSignificant disease other than asthmaSignificant disease other than asthmaSignificant disease other than asthmaSignificant disease other than asthmaSignificant disease other than asthma
TreatmentOnce-daily tiotropium (5 or 2.5 µg) or placebo+Once-daily tiotropium (5 or 2.5 µg) or placeboOnce-daily tiotropium (5 or 2.5 µg) or placeboOnce-daily tiotropium (5 or 2.5 µg) or placeboOnce-daily tiotropium (5 or 2.5 µg) or placebo
Treatment duration12 weeks48 weeks12 weeks48 weeks12 weeks
Sample size102 randomised patients (101 treated, 102 planned); 101 completed patients403 randomised patients (401 treated, 385 planned); 384 completed patients401 randomised patients (400 treated, 375 planned); 392 completed patients398 randomised patients (397 treated, 127 planned per group); 376 completed patients392 randomised patients (392 treated, 375 planned); 388 completed patients

NA: not applicable; ACQ: Asthma Control Questionnaire; IA: interviewer-administered; ICS: inhaled corticosteroid; LTRA: leukotriene receptor antagonist; LABA: long-acting β2-agonist; FEV1: forced expiratory volume in 1 s; % pred: % predicted. #: note that NinoTinA-asthma was a phase 2/3 trial; : the study allowed variation of absolute FEV1 values for visit 1 (pre-bronchodilator) compared with visit 2 (pre-dose) within ±30%; +: in the NinoTinA-asthma study, patients aged 1–4 years at visit 1 were required to use an Aerochamber Plus Flow-Vu valved holding chamber (commonly referred to as a spacer) with a face mask for the inhalation of trial medication to reduce variability and ensure standardised dosing, whereas children aged 5 years at visit 1 were permitted to use the Respimat without a spacer (overall three patients did not use a spacer).